Ligands to cereblon (crbn)

ABSTRACT

Disclosed are compounds with immunomodulatory activity, methods of making the compounds, pharmaceutical compositions containing the compounds, and methods of using the compounds to treat diseases or disorders characterized or mediated by dysfunctional protein activity.

RELATED APPLICATION

This application claims the benefit of priority under 35 U.S.C. § 119(e)to U.S. Provisional Application No. 62/692,167, filed on Jun. 29, 2018,which is incorporated herein by reference in its entirety.

GOVERNMENT LICENSE RIGHTS

This invention was made with government support under grant numberR01CA214608 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

BACKGROUND OF THE INVENTION

The gene that encodes cereblon (CRBN) was first identified in the courseof a study of genes related to memory and learning; the gene wasassigned the name CRBN based on its supposed role in the development ofcerebral tissues and because its expression in the hippocampus amongother areas, is associated with memory and learning processes. Higginset al., Neurol. 63(10):1927-31 (2004).

Cereblon is a 442-amino acid multifunctional protein located in thecytoplasm, nucleus and peripheral membrane of the human brain and othertissues (Wada et al., Biochem. & Biophys. Res. Comm. 477:388-94 (2016)).It interacts with the DNA damage-binding protein-1 (DDB1), Cullin 4(Cul4A and Cul4B), and regulator of Cullins 1 (RoC1) to form thefunctional E3 ubiquitin ligase complex, which is known as theCRL4^(CRBN) E3 ubiquitin ligase complex. Cereblon's role as part of thiscomplex includes targeting proteins for proteolysis (degradation) via aubiquitin-proteasome pathway. See, e.g., Chang et al., Int. J. Biochem.Mol. Biol. 2(3):287-94 (2011).

Cereblon is closely associated with the metabolism and proliferation ofnormal cells as well as tumor cells. On one hand, its existence ensuresnormal metabolic function and normal physiological function of ionchannels, which are important to maintaining cell growth andproliferation. On the other hand, cereblon is also involved in theoccurrence of many diseases, such as cancer. See, generally, Shi et al.,J. Immunol. Res. Article ID 9130608 (2017).

Immunomodulatory drugs (“IMiDs”) are a new class of anti-cancer drugsthat are derived from thalidomide, a drug which has been approved by theFDA for treatment of multiple myeloma. In addition to thalidomideitself, two such thalidomide analogs, lenalidomide and pomalidomide,have been approved by the FDA (and marketed under the names REVLIMID®and POMALYST®, respectively) for treatment of multiple myeloma (amongother diseases). As suggested by their nomenclature, one of the firstknown properties of IMiDs was their immunomodulatory capacity, includingcytokine modulation and T cell co-stimulation (Schafer et al., J.Pharmacol. & Exper. Ther. 305:1222-32 (2003)), resulting ininterleukin-2 production in T cells. Subsequently, IMiDs were shown tohave pleiotropic effects on a wide range of immune cells includingnatural killer (NK) cell activation and B cell and monocyte inhibition(Corral et al., J. Immunol. 163:380-6 (1999)). Even more recently,cereblon has been identified as a common primary target for IMiDs.

For example, it has been reported that members of the Ikaros family oftranscription factors, Ikaros and Aiolos (encoded by the genes IKZF1andIKZF3 respectively, are recruited as protein substrates for CRL4^(CRBN)in T cells in response to treatment with lenalidomide and pomalidomide,resulting in enhanced production of IL-2 and other cytokines thatregulate T cell function. See, Gandhi et al., Br. J. Hematol. 164:811-21(2014). It has also been reported that lenalidomide, but notpomalidomide, induces the degradation of the protein kinase caseinkinase 1α (CK1α), which exploits CK1α haploinsufficiency associated with5q-deletion associated myelodysplastic syndrome. Kronke et al., Nature523:183-8 (2015).

More recently, CRBN-binding compounds named “cereblon modulators” havebeen developed. For example, CC-122, a new chemical entity termed‘pleiotropic pathway modifier’, binds cereblon and promotes degradationof Aiolos and Ikaros in diffuse large B-cell lymphoma (DLBCL) and Tcells in vitro, in vivo, and in patients, resulting in both cellautonomous as well as immunostimulatory effects. See, Hagner et al.,Blood 126(6):779-89 (2016). CC-885 is another new cereblon modulator. Ithas been reported that the anti-tumor activity of this drug, which isbroader than that of thalidomide, lenalidomide and pomalidomide, ismediated by cereblon-dependent ubiquitination and degradation of thetranslation termination factor glutathione S-transferase pi gene 1(GSTP1). See, Matyskiela et al., Nature 535:252-(2016).

The exploitation of cereblon as a mediator in disease treatment has alsoled to the development of hetero-bifunctional PROTACs (PROteolysisTArgeting Chimera) that recruit targeted proteins that are themselvesdisease mediators (e.g., bromodomain-containing protein 4 (BRD4)) toCRL4^(CRBN) E3 ubiquitin ligase, leading to degradation of the targetedprotein. See, e.g., Lu el al, Cell Cancer Biol. 22(6):755-63 (2015).

SUMMARY OF THE INVENTION

A first aspect of the present invention is directed to a compound havinga structure represented by formula (I):

wherein Z is CH₂ or C(O); m and m¹ are independently an integer from0-8; R is H or A; X is H or C(O); Y is absent or NR₁A wherein R₁ is H orC1-C2 alkyl, and wherein if R is H, then X is C(O), m¹ is 1 and Y isNR₁A; and if R is A, then X is H, m¹ is 0 and Y is absent; and wherein Arepresents a group selected from (A1)-(A5):

wherein R₂ is H or C1-C2 alkyl; R₃ is optionally substituted C1-C5alkyl, optionally substituted cyclic (e.g., optionally substitutedC6-C14 aryl, optionally substituted C6-C14 heteroaryl, optionallysubstituted C5-14 carbocyclic and optionally substituted C5-14heterocyclic), or R₂ and R₃ together with the N to which they are boundform an optionally substituted heterocyclic group or an optionallysubstituted heteroaryl group;

wherein R₄ represents an optionally substituted cyclic group (e.g.,optionally substituted C5-C14 carbocyclic group, an optionallysubstituted C6-C14 aryl group, an optionally substituted C5-C14heterocyclic group or an optionally C6-C14 substituted heteroarylgroup);

wherein R₅ represents hydrogen or halo (F, Cl, Br, or I) and R₆represents NR₇R₈ wherein R₇ represents H and R₈ represents an optionallysubstituted C6-C14 aryl group;

wherein R₂ and R₃ are as defined above, and R₉ and R₁₀ each represents Hor each independently represents C or N provided that at least one of R₉and R₁₀ represents N and together with the atoms to which they are boundform an optionally substituted C5-C6 heterocyclic group such asoptionally substituted membered C6 heteroaryl group; or

wherein R₄, R₉ and R₁₀ are as defined above; or a pharmaceuticallyacceptable salt or stereoisomer thereof (also referred to herein as“compound/compounds of the present invention”).

In some embodiments, m and m¹ are independently 0, 1, 2, 3, 4, 5, 6, 7or 8. In certain embodiments, m and m¹ are independently 0, 1, 2, 3, 4,5 or 6.

In some embodiments, Z is CH₂.

Another aspect of the present invention is directed to a pharmaceuticalcomposition that includes a therapeutically effective amount of acompound of the invention, or a pharmaceutically acceptable salt orstereoisomer thereof, and a pharmaceutically acceptable carrier.

A further aspect of the present invention is directed to a method formaking a compound of the invention.

Further aspects of the present invention are directed to methods oftreating diseases or disorders involving aberrant activity of a proteinthat may be a substrate for a complex containing cereblon and thecompound, that entails administration of a therapeutically effectiveamount of a compound of the invention to a subject in need thereof.

Without intending to be bound by any theory of operation, compounds ofthe present invention exert their therapeutic (e.g., anti-cancer)effects or benefits by a combination of anti-proliferative andimmunomodulatory effects. In particular, it is believed that the bindingof the compounds to cereblon confers a differentiated substratespecificity on CRL4^(CRBN) E3 ubiquitin ligase. This diversifiedsubstrate specificity substantially enlarges the types and numbers ofpotential targets, thus offering a wide range of therapeuticapplications. For example, in addition to, or aside from the expressionproducts of Ikaros family zinc finger protein 1 (IKZF1), and IKZF3, andcasein kinase 1 alpha (CK1α), compounds of the present invention mayindirectly target a host of different substrates for cereblon-dependentubiquitination and degradation. Such substrates may include, forexample, family with sequence similarity 83 member F (FAM83F), DTWdomain containing 1 (DTWD1), IKZF2, IKZF4, IKZF5, zinc finger protein 91homolog (ZFP91), ZFP62, ZFP36 ring finger protein like (ZFP36L2), ringfinger protein 166 (RNF166), Ras-related protein Rab-28 (RAB28),glutathione S-transferase pi 1 (GSTP1), GSPT2, mitochondrial importinner membrane translocase subunit Tim10 (TIM10), GDNF inducible zincfinger protein 1 (GZF1), early growth response 1 (EGR1),hyper-methylated in cancer 1 (HIC1), HIC2, insulinoma-associated protein2 (INSM2), odd-skipped related transcription factor 2 (OSR2), proteinpolybromo-1 (PB1), PR domain zinc finger protein 15 (PRD15), spalt liketranscription factor 1 (SALL1), SALL3, SALL4, WIZ, zinc finger and BTBdomain-containing protein 17 (ZBT17), ZBTB39, ZBT41, ZBT49, ZBT7A,ZBT7B, ZBTB2, zinc finger protein interacting with K protein 1 (ZIK1),zinc finger protein 3 (ZNF3), ZNF217, ZNF276, ZNF316, ZNF324B, ZNF335,ZNF397, ZNF407, ZNF408, ZNF462, ZNF483, SNF517, ZNF526, ZNF581, ZNF587,ZNF589, ZNF618, ZNF644, ZNF646, ZNF653, ZN6F54, ZNF692, ZNF724, ZNF771,ZNF782, ZNF784, ZNF814, zinc finger and SCAN domain containing 10(ZSC10), ZSC22, ZC827, and zinc finger with UFM1-specific peptidasedomain (ZUFSP).

Also provided are methods of treating a disease or disordercharacterized or mediated by aberrant activity of a protein selectedfrom the group consisting of casein kinase 1 alpha (CK1α), family withsequence similarity 83 member F (FAM83F), DTW domain containing 1(DTWD1), zinc finger protein 91 homolog (ZFP91), ZFP62, ZFP36 ringfinger protein like (ZFP36L2), ring finger protein 166 (RNF166), Ikarosfamily zinc finger protein 1 (IKZF1), IKZF2, IKZF3, IKZF4, IKZF5,Ras-related protein Rab-28 (RAB28), glutathione S-transferase pi 1(GSTP1), GSPT2, mitochondrial import inner membrane translocase subunitTim10 (TIMM10), GDNF inducible zinc finger protein 1 (GZF1), earlygrowth response 1 (EGR1), hypermethylated in cancer 1 (HIC1), HIC2,insulinoma-associated protein 2 (INSM2), odd-skipped relatedtranscription factor 2 (OSR2), protein polybromo-1 (PB1), PR domain zincfinger protein 15 (PRD15), spalt like transcription factor 1 (SALL1),SALL3, SALL4, WIZ, zinc finger and BTB domain-containing protein 17(ZBT17), ZBT41, ZBT49, ZBT7A, ZBT7B, ZBTB2, ZBTB39, zinc finger proteininteracting with K protein 1 (ZIK1), zinc finger protein 3 (ZNF3),ZNF217, ZNF276, ZNF316, ZNF324B, ZNF335, ZNF397, ZNF407, ZNF408, ZNF462,ZNF483, SNF517, ZNF526, ZNF581, ZNF587, ZNF589, ZNF618, ZNF644, ZNF646,ZNF653, ZNF654, ZNF692, ZNF724, ZNF771, ZNF782, ZNF784, ZNF814, zincfinger and SCAN domain containing 10 (ZSC10), ZSC22, ZC827, and zincfinger with UFM1-specific peptidase domain (ZUFSP), comprisingadministering a therapeutically effective amount of the compound ofFormula I, or a pharmaceutically acceptable salt or stereoisomerthereof, to a subject in need thereof.

In some embodiments, the disease or disorder is characterized ormediated by aberrant activity of IKZF2.

One advantage of the present invention is that the compounds may providean effective therapy in cases where the targets might not be otherwise“druggable” in terms of being directly targeted by any currentgeneration IMiDs. The inventive compounds may also be advantageousrelative to the cereblon-targeted PROTACS which due to their largeflexible linkers can cause pharmacokinetic challenges.

DETAILED DESCRIPTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the subject matter herein belongs. As used in thespecification and the appended claims, unless specified to the contrary,the following terms have the meaning indicated in order to facilitatethe understanding of the present invention.

As used in the description and the appended claims, the singular forms“a”, “an”, and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a composition”includes mixtures of two or more such compositions, reference to “aninhibitor” includes mixtures of two or more such inhibitors, and thelike.

Unless stated otherwise, the term “about” means within 10% (e.g., within5%, 2% or 1%) of the particular value modified by the term “about.”

The transitional term “comprising,” which is synonymous with“including,” “containing,” or “characterized by,” is inclusive oropen-ended and does not exclude additional, unrecited elements or methodsteps. By contrast, the transitional phrase “consisting of” excludes anyelement, step, or ingredient not specified in the claim. Thetransitional phrase “consisting essentially of” limits the scope of aclaim to the specified materials or steps “and those that do notmaterially affect the basic and novel characteristic(s)” of the claimedinvention.

The term “aberrant” as used herein refers to activity that differs fromnormal activity of the protein in a non-pathological state. Suchaberrant activity might be dysfunctional or dysregulated. Thus, the termaberrant may refer to activity or function of a protein that is greateror less relative to a normal healthy subject.

With respect to compounds of the present invention, and to the extentthe following terms are used herein to further describe them, thefollowing definitions apply.

As used herein, the term “alkyl” refers to a saturated linear orbranched-chain monovalent hydrocarbon radical. In one embodiment, thealkyl radical is a C₁-C₁₈ group. In other embodiments, the alkyl radicalis a C₀-C₆, C₀-C₅, C₀-C₃, C₁-C₁₂, C₁-C₈, C₁-C₆, C₁-C₅, C₁- C₄ or C₁-C₃group (wherein C₀ alkyl refers to a bond). Examples of alkyl groupsinclude methyl, ethyl, 1-propyl, 2-propyl, i-propyl, 1-butyl,2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, n-pentyl,2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl,3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl,3,3-dimethyl-2-butyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.In some embodiments, an alkyl group is a C₁-C₃ alkyl group. In someembodiments, an alkyl group is a C₁-C₂ alkyl group.

As used herein, the term “alkylene” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing nounsaturation and having from one to 12 carbon atoms, for example,methylene, ethylene, propylene, n-butylene, and the like. The alkylenechain may be attached to the rest of the molecule through a single bondand to the radical group through a single bond. In some embodiments, thealkylene group contains one to 8 carbon atoms (C₁-C₈ alkylene). In otherembodiments, an alkylene group contains one to 5 carbon atoms (C₁-C₅alkylene). In other embodiments, an alkylene group contains one to 4carbon atoms (C₁-C₄ alkylene). In other embodiments, an alkylenecontains one to three carbon atoms (C₁-C₃ alkylene). In otherembodiments, an alkylene group contains one to two carbon atoms (C₁-C₂alkylene). In other embodiments, an alkylene group contains one carbonatom (C₁ alkylene).

As used herein, the term “haloalkyl” refers to an alkyl group as definedherein that is substituted with one or more (e.g., 1, 2, 3, or 4) halogroups.

As used herein, the term “alkenyl” refers to a linear or branched-chainmonovalent hydrocarbon radical with at least one carbon-carbon doublebond. An alkenyl includes radicals having “cis” and “trans”orientations, or alternatively, “E” and “Z” orientations. In oneexample, the alkenyl radical is a C₂-C₁₈ group. In other embodiments,the alkenyl radical is a C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₃ group.Examples include ethenyl or vinyl, prop-1-enyl, prop-2-enyl,2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl,buta-1,3-dienyl, 2-methylbuta-1,3-diene, hex-1-enyl, hex-2-enyl,hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl.

As used herein, the term “alkynyl” refers to a linear or branchedmonovalent hydrocarbon radical with at least one carbon-carbon triplebond. In one example, the alkynyl radical is a C₂-C₁₈ group. In otherexamples, the alkynyl radical is C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₃.Examples include ethynyl prop-1-ynyl, prop-2-ynyl, but-1-ynyl,but-2-ynyl and but-3-ynyl.

The terms “alkoxyl” or “alkoxy” as used herein refer to an alkyl group,as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as can berepresented by one of —O-alkyl, —O-alkenyl, and —O-alkynyl.

As used herein, the term “halogen” (or “halo” or “halide”) refers tofluorine, chlorine, bromine, or iodine.

As used herein, the term “ester” is represented by the formula OC(O)Z¹or C(O)OZ¹, where Z¹ may be an alkyl, halogenated alkyl, alkenyl,alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl,or heterocycloalkenyl group, all as described herein.

As used herein, the term “ether” is represented by the formula Z¹OZ²,where Z¹ and Z² can be, independently, an alkyl, halogenated alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl group, all as described herein.

As used herein, the term “ketone” is represented by the formulaZ¹C(O)Z², where A¹ and A² independently represent alkyl, halogenatedalkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, or heterocycloalkenyl group, all as described herein.

As used herein, the term “sulfonyl” refers to the sulfo-oxo grouprepresented by the formula —S(O)₂Z¹, where Z¹ may be hydrogen, an alkyl,halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group, all asdescribed herein.

As used herein, the term “sulfonylamino” (or “sulfonamide”) isrepresented by the formula —S(O)₂NH₂.

As used herein, the term “cyclic group” broadly refers to any group thatused alone or as part of a larger moiety, contains a saturated,partially saturated or aromatic ring system e.g., carbocyclic(cycloalkyl, cycloalkenyl), heterocyclic (heterocycloalkyl,heterocycloalkenyl), aryl and heteroaryl groups. Cyclic groups may haveone or more (e.g., fused) ring systems. Thus, for example, a cyclicgroup can contain one or more carbocyclic, heterocyclic, aryl orheteroaryl groups.

As used herein, the term “carbocyclic” (also “carbocyclyl”) refers to agroup that used alone or as part of a larger moiety, contains asaturated, partially unsaturated, or aromatic ring system having 3 to 20carbon atoms, that is alone or part of a larger moiety (e.g., analkcarbocyclic group). The term carbocyclyl includes mono-, bi-, tri-,fused, bridged, and spiro-ring systems, and combinations thereof. In oneembodiment, carbocyclyl includes 3 to 15 carbon atoms (C₃-C₁₅). In oneembodiment, carbocyclyl includes 3 to 12 carbon atoms (C₃-C₁₂). Inanother embodiment, carbocyclyl includes C₃-C₈, C₃-C₁₀ or C₅-C₁₀. Inanother embodiment, carbocyclyl, as a monocycle, includes C₃-C₈, C₃-C₆or C₅-C₆. In some embodiments, carbocyclyl, as a bicycle, includesC₇-C₁₂. In another embodiment, carbocyclyl, as a spiro system, includesC₅-C₁₂. Representative examples of monocyclic carbocyclyls includecyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,perdeuteriocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl,1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecyl, phenyl, and cyclododecyl; bicycliccarbocyclyls having 7 to 12 ring atoms include [4,3], [4,4], [4,5],[5,5], [5,6] or [6,6] ring systems, such as for examplebicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, naphthalene, andbicyclo[3.2.2]nonane. Representative examples of spiro carbocyclylsinclude spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane,spiro[2.5]octane and spiro[4.5]decane. The term carbocyclyl includesaryl ring systems as defined herein. The term carbocyclyl also includescycloalkyl rings (e.g., saturated or partially unsaturated mono-, bi-,or spiro-carbocycles). The term carbocyclic group also includes acarbocyclic ring fused to one or more (e.g., 1, 2 or 3) different cyclicgroups (e.g., aryl or heterocyclic rings), where the radical or point ofattachment is on the carbocyclic ring.

Thus, the term carbocyclic also embraces carbocyclylalkyl groups whichas used herein refer to a group of the formula —R^(c)-carbocyclyl whereR^(c) is an alkylene chain. The term carbocyclic also embracescarbocyclylalkoxy groups which as used herein refer to a group bondedthrough an oxygen atom of the formula —O—R^(c)-carbocyclyl where R^(c)is an alkylene chain.

As used herein, the term “heterocyclyl” refers to a “carbocyclyl” thatused alone or as part of a larger moiety, contains a saturated,partially unsaturated or aromatic ring system, wherein one or more(e.g., 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom(e.g., O, N, N(O), S, S(O), or S(O)₂). The term heterocyclyl includesmono-, bi-, tri-, fused, bridged, and spiro-ring systems, andcombinations thereof. In some embodiments, a heterocyclyl refers to a 3to 15 membered heterocyclyl ring system. In some embodiments, aheterocyclyl refers to a 3 to 12 membered heterocyclyl ring system. Insome embodiments, a heterocyclyl refers to a saturated ring system, suchas a 3 to 12 membered saturated heterocyclyl ring system. In someembodiments, a heterocyclyl refers to a heteroaryl ring system, such asa 5 to 14 membered heteroaryl ring system. The term heterocyclyl alsoincludes C₃-C₈ heterocycloalkyl, which is a saturated or partiallyunsaturated mono-, bi-, or spiro-ring system containing 3-8 carbons andone or more (1, 2, 3 or 4) heteroatoms.

In some embodiments, a heterocyclyl group includes 3-12 ring atoms andincludes monocycles, bicycles, tricycles and Spiro ring systems, whereinthe ring atoms are carbon, and one to 5 ring atoms is a heteroatom suchas nitrogen, sulfur or oxygen. In some embodiments, heterocyclylincludes 3- to 7-membered monocycles having one or more heteroatomsselected from nitrogen, sulfur or oxygen. In some embodiments,heterocyclyl includes 4- to 6-membered monocycles having one or moreheteroatoms selected from nitrogen, sulfur or oxygen. In someembodiments, heterocyclyl includes 3-membered monocycles. In someembodiments, heterocyclyl includes 4-membered monocycles. In someembodiments, heterocyclyl includes 5-6 membered monocycles. In someembodiments, the heterocyclyl group includes 0 to 3 double bonds. In anyof the foregoing embodiments, heterocyclyl includes 1, 2, 3 or 4heteroatoms. Any nitrogen or sulfur heteroatom may optionally beoxidized (e.g., NO, SO, SO₂), and any nitrogen heteroatom may optionallybe quaternized (e.g., [NR₄]⁺Cl⁻, [NR₄]⁺OH⁻). Representative examples ofheterocyclyls include oxiranyl, aziridinyl, thiiranyl, azetidinyl,oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl,dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydropyranyl, dihydrothienyl,tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl,tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl,oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl,azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl,1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl,tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl,1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl,4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl,4,5,6,7-tetrahydrobenzo[d]imidazolyl,1,6-dihydroimidazol[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, oxazinyl,thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl,thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl,dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl,pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl,piperazindionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl,3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl,3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl,azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl,8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl,8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane,azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl,1-azaspiro[4.5]decan-2-only, azaspiro[5.5]undecanyl, tetrahydroindolyl,octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl,1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocyclylscontaining a sulfur or oxygen atom and one to three nitrogen atoms arethiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide,thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl,oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl. Example 5-membered ringheterocyclyls containing 2 to 4 nitrogen atoms include imidazolyl, suchas imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl;1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as1H-tetrazol-5-yl. Representative examples of benzo-fused 5-memberedheterocyclyls are benzoxazol-2-yl, benzthiazol-2-yl andbenzimidazol-2-yl. Example 6-membered heterocyclyls contain one to threenitrogen atoms and optionally a sulfur or oxygen atom, for examplepyridyl, such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, suchas pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as 1,3,4-triazin-2-yland 1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, andpyrazinyl. The pyridine N-oxides and pyridazine N-oxides and thepyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the1,3,4-triazin-2-yl groups, are yet other examples of heterocyclylgroups. In some embodiments, a heterocyclic group includes aheterocyclic ring fused to one or more (e.g., 1, 2 or 3) differentcyclic groups (e.g., carbocyclic rings or heterocyclic rings), where theradical or point of attachment is on the heterocyclic ring, and in someembodiments wherein the point of attachment is a heteroatom contained inthe heterocyclic ring.

Thus, the term heterocyclic embraces N-heterocyclyl groups which as usedherein refer to a heterocyclyl group containing at least one nitrogenand where the point of attachment of the heterocyclyl group to the restof the molecule is through a nitrogen atom in the heterocyclyl group.Representative examples of N-heterocyclyl groups include 1-morpholinyl,1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl,imidazolinyl and imidazolidinyl. The term heterocyclic also embracesC-heterocyclyl groups which as used herein refer to a heterocyclyl groupcontaining at least one heteroatom and where the point of attachment ofthe heterocyclyl group to the rest of the molecule is through a carbonatom in the heterocyclyl group. Representative examples ofC-heterocyclyl radicals include 2-morpholinyl, 2- or 3- or4-piperidinyl, 2-piperazinyl, and 2- or 3-pyrrolidinyl. The termheterocyclic also embraces heterocyclylalkyl groups which as disclosedabove refer to a group of the formula —R^(c)-heterocyclyl where R^(c) isan alkylene chain. The term heterocyclic also embracesheterocyclylalkoxy groups which as used herein refer to a radical bondedthrough an oxygen atom of the formula —O—R^(c)-heterocyclyl where R^(c)is an alkylene chain.

As used herein, the term “aryl” used alone or as part of a larger moiety(e.g., “aralkyl”, wherein the terminal carbon atom on the alkyl group isthe point of attachment, e.g., a benzyl group), “aralkoxy” wherein theoxygen atom is the point of attachment, or “aroxyalkyl” wherein thepoint of attachment is on the aryl group) refers to a group thatincludes monocyclic, bicyclic or tricyclic, carbon ring system, thatincludes fused rings, wherein at least one ring in the system isaromatic. In some embodiments, the aralkoxy group is a benzoxy group.The term “aryl” may be used interchangeably with the term “aryl ring”.In one embodiment, aryl includes groups having 6-18 carbon atoms. Inanother embodiment, aryl includes groups having 6-10 carbon atoms.Examples of aryl groups include phenyl, naphthyl, anthracyl, biphenyl,phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl,2,3-dihydro-1H-indenyl, and the like, which may be substituted orindependently substituted by one or more substituents described herein.A particular aryl is phenyl. In some embodiments, an aryl group includesan aryl ring fused to one or more (e.g., 1, 2 or 3) different cyclicgroups (e.g., carbocyclic rings or heterocyclic rings), where theradical or point of attachment is on the aryl ring.

Thus, the term aryl embraces aralkyl groups (e.g., benzyl) which asdisclosed above refer to a group of the formula —R^(c)-aryl where R^(c)is an alkylene chain such as methylene or ethylene. In some embodiments,the aralkyl group is an optionally substituted benzyl group. The termaryl also embraces aralkoxy groups which as used herein refer to a groupbonded through an oxygen atom of the formula —O—R^(c)-aryl where R^(c)is an alkylene chain such as methylene or ethylene.

As used herein, the term “heteroaryl” used alone or as part of a largermoiety (e.g., “heteroarylalkyl” (also “heteroaralkyl”), or“heteroarylalkoxy” (also “heteroaralkoxy”), refers to a monocyclic,bicyclic or tricyclic ring system having 5 to 14 ring atoms, wherein atleast one ring is aromatic and contains at least one heteroatom. In oneembodiment, heteroaryl includes 4-6 membered monocyclic aromatic groupswhere one or more ring atoms is nitrogen, sulfur or oxygen that isindependently optionally substituted. In another embodiment, heteroarylincludes 5-6 membered monocyclic aromatic groups where one or more ringatoms is nitrogen, sulfur or oxygen. Representative examples ofheteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl,oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl,tetrazolo[1,5-b]pyridazinyl, purinyl, benzoxazolyl, benzofuryl,benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl,indolyl, 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3-oxazol-2-yl,1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl,1H-tetrazol-5-yl, 1,2,3-triazol-5-yl, and pyrid-2-yl N-oxide. The term“heteroaryl” also includes groups in which a heteroaryl is fused to oneor more cyclic (e.g., carbocyclyl, or heterocyclyl) rings, where theradical or point of attachment is on the heteroaryl ring. Nonlimitingexamples include indolyl, isoindolyl, benzothienyl, benzofuranyl,dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl,isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl andpyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono-, bi-or tri-cyclic. In some embodiments, a heteroaryl group includes aheteroaryl ring fused to one or more (e.g., 1, 2 or 3) different cyclicgroups (e.g., carbocyclic rings or heterocyclic rings), where theradical or point of attachment is on the heteroaryl ring, and in someembodiments wherein the point of attachment is a heteroatom contained inthe heterocyclic ring.

Thus, the term heteroaryl embraces N-heteroaryl groups which as usedherein refer to a heteroaryl group as defined above containing at leastone nitrogen and where the point of attachment of the heteroaryl groupto the rest of the molecule is through a nitrogen atom in the heteroarylgroup. The term heteroaryl also embraces C-heteroaryl groups which asused herein refer to a heteroaryl group as defined above and where thepoint of attachment of the heteroaryl group to the rest of the moleculeis through a carbon atom in the heteroaryl group. The term heteroarylalso embraces heteroarylalkyl groups which as disclosed above refer to agroup of the formula —R^(c)-heteroaryl, where R^(c) is an alkylene chainas defined above. The term heteroaryl also embraces heteroaralkoxy (orheteroarylalkoxy) groups which as used herein refer to a group bondedthrough an oxygen atom of the formula —O—R^(c)-heteroaryl, where R^(c)is an alkylene group as defined above.

Any of the groups described herein may be substituted or unsubstituted.As used herein, the term “substituted” broadly refers to all permissiblesubstituents with the implicit proviso that such substitution is inaccordance with permitted valence of the substituted atom and thesubstituent, and that the substitution results in a stable compound,i.e. a compound that does not spontaneously undergo transformation suchas by rearrangement, cyclization, elimination, etc. Representativesubstituents include halogens, hydroxyl groups, and any other organicgroupings containing any number of carbon atoms, e.g., 1-14 carbonatoms, and which may include one or more (e.g., 1 2 3, or 4) heteroatomssuch as oxygen, sulfur, and nitrogen grouped in a linear, branched, orcyclic structural format.

Representative examples of substituents may thus include alkyl,substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cyclic, substituted cyclic,carbocyclic, substituted carbocyclic, heterocyclic, substitutedheterocyclic, aryl (e.g., benzyl and phenyl), substituted aryl (e.g.,substituted benzyl or phenyl), heteroaryl, substituted heteroaryl,aralkyl, substituted aralkyl, halo, hydroxyl, aryloxy, substitutedaryloxy, alkylthio, substituted alkylthio, arylthio, substitutedarylthio, cyano, carbonyl, substituted carbonyl, carboxyl, substitutedcarboxyl, amino, substituted amino, amido, substituted amido, sulfonyl,substituted sulfonyl, amino acid, and peptide groups.

Broadly, compounds of the present invention have a structure representedby formula (I):

wherein Z is CH₂ or C(O); m and m¹ are independently an integer from0-8; R is H or A; X is H or C(O); Y is absent or NR₁A wherein R₁ is H orC1-C2 alkyl, and wherein if R is H, then X is C(O), m¹ is 1 and Y isNR₁A; and if R is A, then X is H, m¹ is 0 and Y is absent; and wherein Arepresents

wherein R₂ is H or C1-C2 alkyl; R₃ is optionally substituted C1-C5alkyl, optionally substituted C6-C14 aryl, optionally substituted C6-C14heteroaryl, optionally substituted C5-C14 carbocyclic or optionallysubstituted C5-C14 heterocyclic, or R₂ and R₃ together with the N towhich they are bound form an optionally substituted C6-C14 heterocyclicgroup or an optionally substituted C6-C14 heteroaryl group;

wherein R₄ represents an optionally substituted cyclic group, e.g., anoptionally substituted C5-C14 carbocyclic group, an optionallysubstituted C6-C14 aryl group, an optionally substituted C5-C14heterocyclic group or an optionally substituted C6-C14 heteroaryl group;

wherein R₅ represents hydrogen or halo and R₆ represents NR₇R₈ whereinR₇ represents H and R₈ represents an optionally substituted C6-C14 arylgroup;

wherein R₂ and R₃ are as defined above, and R₉ and R₁₀ each represents Hor each independently represents C or N provided that at least one of R₉and R₁₀ represents N and together with the atoms to which they are boundform an optionally substituted C5-C6 heterocyclic group such asoptionally substituted C6 heteroaryl group; or

wherein R₄, R₉ and R₁₀ are as defined above, or a pharmaceuticallyacceptable salt or stereoisomer thereof.

In some embodiments, m and m¹ are independently 0, 1, 2, 3, 4, 5, 6, 7or 8. In certain embodiments, m and m¹ are independently 0, 1, 2, 3, 4,5 or 6.

In some embodiments, wherein m is 0, R is H, X is C(O), m¹ is 1, Y isNR₁A and R₁ is H, the compounds of formula (I) have a structurerepresented by formula (Ia):

wherein A and Z are as defined above, or a pharmaceutically acceptablesalt or stereoisomer thereof.

In some embodiments, wherein A is represented by A1, the compounds offormula (Ia) have a structure represented by formula (Ia1):

wherein R₂ and R₃ are as defined above, or a pharmaceutically acceptablesalt or stereoisomer thereof.

In some embodiments, wherein R₃ represents aryl (e.g., phenyl) orsubstituted aryl (e.g., substituted phenyl), the compounds of formula(Ia1) have a structure represented by formula (Ia1a):

wherein m₁ is 0 or 1, and R₁₁ and R₁₂ independently represent H, halo,CF₃, or C1-C2 alkoxy, or wherein R₁₁ and R₁₂ each independentlyrepresents C or a heteroatom (e.g., O, N or S) and together with theatoms to which they are bound form an optionally substituted cyclicgroup, e.g., C5-C14 carbocyclic, C5-C14 heterocyclic, C6-C14 aryl orC6-C14 heteroaryl group (but consistent with use of the term “aryl”, theoverall ring structure is defined as an optionally substituted arylgroup), or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, wherein R₃ represents an optionally substitutedheterocyclic group, the compound of formula (Ia1) has a structurerepresented by formula (Ia1b):

wherein R₂ is as defined above and R₁₃ represents H or optionallysubstituted C1-C5 alkyl, optionally substituted C6-C14 aryl, optionallysubstituted C6-C14 heteroaryl, optionally substituted C5-C14 carbocyclicor optionally substituted C5-C14 heterocyclic, or a pharmaceuticallyacceptable salt or stereoisomer thereof.

In some embodiments, when m is 0 and R₂ and R₃ together with the atomsto which they are bound form an optionally C5-C14 heterocyclic such asan optionally substituted C6-C14 heteroaryl group, the compound offormula (Ia1) has a structure represented by formula (Ia1c):

wherein R₁₃ is as defined above, or a pharmaceutically acceptable saltor stereoisomer thereof.

In some embodiments, wherein A is represented by A2, the compound offormula (Ia) has a structure as represented by formula (Ia2):

wherein R₄ is as defined above, or a pharmaceutically acceptable salt orstereoisomer thereof.

In some embodiments, wherein m and m¹ are 0, X is H, Y is absent and Ris A, the compound of formula (I) has a structure as represented byformula (Ib):

or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, wherein A is represented by A1, the compound offormula (Ib) has a structure as represented by formula (Ib1):

wherein R₂ and R₃ are as defined above, or a pharmaceutically acceptablesalt or stereoisomer thereof.

In some embodiments, when R₃ is an optionally substituted aryl (e.g.,phenyl), the compound of formula (Ib1) has a structure represented byformula (Ib1a):

wherein m₁ is 0 or 1 and R₂, R₁₁ and R₁₂ are as defined above, or apharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the compound of formula (Ib1) has a structurerepresented by formula (Ib1b):

wherein m₁ is 0 or 1, R₂ is as defined above and R₃ represents anoptionally substituted C5-C14 heterocyclic group, or a pharmaceuticallyacceptable salt or stereoisomer thereof.

In some embodiments, wherein R₂ and R₃ together with the atoms to whichthey are bound form an optionally substituted heterocyclic group such asan optionally substituted heteroaryl group, the compound of formula(Ib1) has a structure represented by formula (Ib1c):

wherein R₁₃ is as defined above, or a pharmaceutically acceptable saltor stereoisomer thereof.

In some embodiments, wherein A is represented by A2, the compound offormula (Ib) has a structure as represented by formula (Ib2):

wherein R₄ is as defined above, or a pharmaceutically acceptable salt orstereoisomer thereof.

In some embodiments, wherein A is represented by A3, the compound offormula (Ib) has a structure as represented by formula (Ib3):

wherein R₅ and R₆ are as defined above, or a pharmaceutically acceptablesalt or stereoisomer thereof.

In some embodiments, wherein A is represented by A4, the compound offormula (Ib) has a structure as represented by formula (Ib4):

wherein R₂, R₃, R₉ and R₁₀ are as defined above, or a pharmaceuticallyacceptable salt or stereoisomer thereof.

In some embodiments, wherein A is represented by A5, the compound offormula (Ib) has a structure as represented by formula (Ib5):

wherein R₄, R₉ and R₁₀ are as defined above, or a pharmaceuticallyacceptable salt or stereoisomer thereof.

In some embodiments, wherein X is H, m¹ is 0, R is A and Y is absent,the compound of formula (I) has a structure as represented by formula(Ic):

or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, wherein A is represented by A3, the compound offormula (Ic) has a structure as represented by formula (Ic1):

wherein R₅ and R₆ are as defined above, or a pharmaceutically acceptablesalt or stereoisomer thereof.

With respect to the compounds of the present invention, representativeexamples of R₃, R₄ and R₈ are as follows:

With respect to the compounds of the present invention, representativeexamples of NR₂R₃ groups are as follows:

With respect to the compounds of the present invention, representativeexamples of optionally substituted C5-C6 heterocyclic groups formed byR₉ and R₁₀ are as follows:

In some embodiments, Z is CH₂.

In some embodiments, compounds of the present invention are as follows:

or a pharmaceutically acceptable salt or stereoisomer thereof.

Compounds of the present application may be in the form of a free acidor free base, or a pharmaceutically acceptable salt. As used herein, theterm “pharmaceutically acceptable” in the context of a salt refers to asalt of the compound that does not abrogate the biological activity orproperties of the compound, and is relatively non-toxic, i.e., thecompound in salt form may be administered to a subject without causingundesirable biological effects (such as dizziness or gastric upset) orinteracting in a deleterious manner with any of the other components ofthe composition in which it is contained. The term “pharmaceuticallyacceptable salt” refers to a product obtained by reaction of thecompound of the present invention with a suitable acid or a base.Examples of pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic bases such asLi, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate,isonicotinate, acetate, lactate, salicylate, citrate, tartrate,pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate,fumarate, gluconate, glucaronate, saccharate, formate, benzoate,glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,4-methylbenzenesulfonate or p-toluenesulfonate salts and the like.Certain compounds of the invention can form pharmaceutically acceptablesalts with various organic bases such as lysine, arginine, guanidine,diethanolamine or metformin.

In some embodiments, a compound of the present invention is an isotopicderivative in that it has at least one desired isotopic substitution ofan atom, at an amount above the natural abundance of the isotope, i.e.,enriched. In one embodiment, the compound includes deuterium or multipledeuterium atoms. Substitution with heavier isotopes such as deuterium,i.e. ²H, may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example, increased in vivo half-life orreduced dosage requirements, and thus may be advantageous in somecircumstances.

Compounds of the present invention may have at least one chiral centerand thus may be in the form of a stereoisomer, which as used herein,embraces all isomers of individual compounds that differ only in theorientation of their atoms in space. The term stereoisomer includesmirror image isomers (enantiomers which include the (R-) or (S-)configurations of the compounds), mixtures of mirror image isomers(physical mixtures of the enantiomers, and racemates or racemicmixtures) of compounds, geometric (cis/trans or E/Z, R/S) isomers ofcompounds and isomers of compounds with more than one chiral center thatare not mirror images of one another (diastereoisomers). The chiralcenters of the compounds may undergo epimerization in vivo; thus, forthese compounds, administration of the compound in its (R-) form isconsidered equivalent to administration of the compound in its (S-)form. Accordingly, the compounds of the present application may be madeand used in the form of individual isomers and substantially free ofother isomers, or in the form of a mixture of various isomers, e.g.,racemic mixtures of stereoisomers.

In addition, the compounds of the present invention embrace the use ofN-oxides, crystalline forms (also known as polymorphs), activemetabolites of the compounds having the same type of activity,tautomers, and unsolvated as well as solvated forms withpharmaceutically acceptable solvents such as water, ethanol, and thelike, of the compounds. The solvated forms of the conjugates presentedherein are also considered to be disclosed herein.

Methods of Synthesis

In another aspect, the present invention is directed to a method formaking a compound of the present invention, or a pharmaceuticallyacceptable salt or stereoisomer thereof. Broadly, the inventivecompounds or pharmaceutically-acceptable salts or stereoisomers thereofmay be prepared by any process known to be applicable to the preparationof chemically related compounds. The compounds of the present inventionwill be better understood in connection with the synthetic schemes thatdescribed in various working examples and which illustrate nonlimitingmethods by which the compounds of the invention may be prepared.

Pharmaceutical Compositions

Another aspect of the present invention is directed to a pharmaceuticalcomposition that includes a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt orstereoisomer thereof, and a pharmaceutically acceptable carrier. Theterm “pharmaceutically acceptable carrier,” as known in the art, refersto a pharmaceutically acceptable material, composition or vehicle,suitable for administering compounds of the present invention tomammals. Suitable carriers may include, for example, liquids (bothaqueous and non-aqueous alike, and combinations thereof), solids,encapsulating materials, gases, and combinations thereof (e.g.,semi-solids), and gases, that function to carry or transport thecompound from one organ, or portion of the body, to another organ, orportion of the body. A carrier is “acceptable” in the sense of beingphysiologically inert to and compatible with the other ingredients ofthe formulation and not injurious to the subject or patient. Dependingon the type of formulation, the composition may include one or morepharmaceutically acceptable excipients.

Broadly, compounds of the present invention may be formulated into agiven type of composition in accordance with conventional pharmaceuticalpractice such as conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping andcompression processes (see, e.g., Remington: The Science and Practice ofPharmacy (20th ed.), ed. A. R. Gennaro, Lippincott Williams & Wilkins,2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrickand J. C. Boylan, 1988-1999, Marcel Dekker, New York). The type offormulation depends on the mode of administration which may includeenteral (e.g., oral, buccal, sublingual and rectal), parenteral (e.g.,subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), andintrasternal injection, or infusion techniques, intra-ocular,intra-arterial, intramedullary, intrathecal, intraventricular,transdermal, interdermal, intravaginal, intraperitoneal, mucosal, nasal,intratracheal instillation, bronchial instillation, and inhalation) andtopical (e.g., transdermal). In general, the most appropriate route ofadministration will depend upon a variety of factors including, forexample, the nature of the agent (e.g., its stability in the environmentof the gastrointestinal tract), and/or the condition of the subject(e.g., whether the subject is able to tolerate oral administration). Forexample, parenteral (e.g., intravenous) administration may also beadvantageous in that the compound may be administered relatively quicklysuch as in the case of a single-dose treatment and/or an acutecondition.

In some embodiments, the compositions are formulated for oral orintravenous administration (e.g., systemic intravenous injection).

Accordingly, compounds of the present invention may be formulated intosolid compositions (e.g., powders, tablets, dispersible granules,capsules, cachets, and suppositories), liquid compositions (e.g.,solutions in which the compound is dissolved, suspensions in which solidparticles of the compound are dispersed, emulsions, and solutionscontaining liposomes, micelles, or nanoparticles, syrups and elixirs);semi-solid compositions (e.g., gels, suspensions and creams); and gases(e.g., propellants for aerosol compositions). Compounds may also beformulated for rapid, intermediate or extended release.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with a carrier such as sodium citrate or dicalciumphosphate and an additional carrier or excipient such as a) fillers orextenders such as starches, lactose, sucrose, glucose, mannitol, andsilicic acid, b) binders such as, for example, methylcellulose,microcrystalline cellulose, hydroxypropylmethylcellulose,carboxymethylcellulose, sodium carboxymethylcellulose, alginates,gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants suchas glycerol, d) disintegrating agents such as crosslinked polymers(e.g., crosslinked polyvinylpyrrolidone (crospovidone), crosslinkedsodium carboxymethyl cellulose (croscarmellose sodium), sodium starchglycolate, agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also include buffering agents. Solid compositions of asimilar type may also be employed as fillers in soft and hard-filledgelatin capsules using such excipients as lactose or milk sugar as wellas high molecular weight polyethylene glycols and the like. The soliddosage forms of tablets, dragees, capsules, pills, and granules can beprepared with coatings and shells such as enteric coatings and othercoatings. They may further contain an opacifying agent.

In some embodiments, compounds of the present invention may beformulated in a hard or soft gelatin capsule. Representative excipientsthat may be used include pregelatinized starch, magnesium stearate,mannitol, sodium stearyl fumarate, lactose anhydrous, microcrystallinecellulose and croscarmellose sodium. Gelatin shells may include gelatin,titanium dioxide, iron oxides and colorants.

Liquid dosage forms for oral administration include solutions,suspensions, emulsions, micro-emulsions, syrups and elixirs. In additionto the compound, the liquid dosage forms may contain an aqueous ornon-aqueous carrier (depending upon the solubility of the compounds)commonly used in the art such as, for example, water or other solvents,solubilizing agents and emulsifiers such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils(in particular, cottonseed, groundnut, corn, germ, olive, castor, andsesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycolsand fatty acid esters of sorbitan, and mixtures thereof. Oralcompositions may also include an excipients such as wetting agents,suspending agents, coloring, sweetening, flavoring, and perfumingagents.

Injectable preparations may include sterile aqueous solutions oroleaginous suspensions. They may be formulated according to standardtechniques using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution, suspension or emulsion in a nontoxic parenterallyacceptable diluent or solvent, for example, as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution, U.S.P. and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose any blandfixed oil can be employed including synthetic mono- or diglycerides. Inaddition, fatty acids such as oleic acid are used in the preparation ofinjectables. The injectable formulations can be sterilized, for example,by filtration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use. The effect of the compound may be prolonged byslowing its absorption, which may be accomplished by the use of a liquidsuspension or crystalline or amorphous material with poor watersolubility. Prolonged absorption of the compound from a parenterallyadministered formulation may also be accomplished by suspending thecompound in an oily vehicle.

In certain embodiments, compounds of present invention may beadministered in a local rather than systemic manner, for example, viainjection of the conjugate directly into an organ, often in a depotpreparation or sustained release formulation. In specific embodiments,long acting formulations are administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection.Injectable depot forms are made by forming microencapsule matrices ofthe compound in a biodegradable polymer, e.g.,polylactide-polyglycolides, poly(orthoesters) and poly(anhydrides). Therate of release of the compound may be controlled by varying the ratioof compound to polymer and the nature of the particular polymeremployed. Depot injectable formulations are also prepared by entrappingthe compound in liposomes or microemulsions that are compatible withbody tissues. Furthermore, in other embodiments, the compound isdelivered in a targeted drug delivery system, for example, in a liposomecoated with organ-specific antibody. In such embodiments, the liposomesare targeted to and taken up selectively by the organ.

The inventive compounds may be formulated for buccal or sublingualadministration, examples of which include tablets, lozenges and gels.

The compounds may be formulated for administration by inhalation.Various forms suitable for administration by inhalation includeaerosols, mists or powders. Pharmaceutical compositions may be deliveredin the form of an aerosol spray presentation from pressurized packs or anebulizer, with the use of a suitable propellant (e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas). Insome embodiments, the dosage unit of a pressurized aerosol may bedetermined by providing a valve to deliver a metered amount. In someembodiments, capsules and cartridges including gelatin, for example, foruse in an inhaler or insufflator, may be formulated containing a powdermix of the compound and a suitable powder base such as lactose orstarch.

Compounds of the present invention may be formulated for topicaladministration which as used herein, refers to administrationintradermally by application of the formulation to the epidermis. Thesetypes of compositions are typically in the form of ointments, pastes,creams, lotions, gels, solutions and sprays.

Representative examples of carriers useful in formulating compositionsfor topical application include solvents (e.g., alcohols, poly alcohols,water), creams, lotions, ointments, oils, plasters, liposomes, powders,emulsions, microemulsions, and buffered solutions (e.g., hypotonic orbuffered saline). Creams, for example, may be formulated using saturatedor unsaturated fatty acids such as stearic acid, palmitic acid, oleicacid, palmito-oleic acid, cetyl, or oleyl alcohols. Creams may alsocontain a non-ionic surfactant such as polyoxy-40-stearate.

In some embodiments, the topical formulations may also include anexcipient, an example of which is a penetration enhancing agent. Theseagents are capable of transporting a pharmacologically active compoundthrough the stratum corneum and into the epidermis or dermis,preferably, with little or no systemic absorption. A wide variety ofcompounds have been evaluated 1 as to their effectiveness in enhance

ng the rate of penetration of drugs through the skin. See, for example,Percutaneous Penetration Enhancers, Maibach H. I. and Smith H. E.(eds.), CRC Press, Inc., Boca Raton, Fla. (1995), which surveys the useand testing of various skin penetration enhancers, and Buyuktimkin etal., Chemical Means of Transdermal Drug Permeation Enhancement inTransdermal and Topical Drug Delivery Systems, Gosh T. K., Pfister W.R., Yum S. I. (Eds.), Interpharm Press Inc., Buffalo Grove, Ill. (1997).Representative examples of penetration enhancing agents includetriglycerides (e.g., soybean oil), aloe compositions (e.g., aloe-veragel), ethyl alcohol, isopropyl alcohol, octolyphenylpolyethylene glycol,oleic acid, polyethylene glycol 400, propylene glycol,N-decylmethylsulfoxide, fatty acid esters (e.g., isopropyl myristate,methyl laurate, glycerol monooleate, and propylene glycol monooleate),and N-methylpyrrolidone.

Representative examples of yet other excipients that may be included intopical as well as in other types of formulations (to the extent theyare compatible), include preservatives, antioxidants, moisturizers,emollients, buffering agents, solubilizing agents, skin protectants, andsurfactants. Suitable preservatives include alcohols, quaternary amines,organic acids, parabens, and phenols. Suitable antioxidants includeascorbic acid and its esters, sodium bisulfite, butylatedhydroxytoluene, butylated hydroxyanisole, tocopherols, and chelatingagents like EDTA and citric acid. Suitable moisturizers includeglycerine, sorbitol, polyethylene glycols, urea, and propylene glycol.Suitable buffering agents include citric, hydrochloric, and lactic acidbuffers. Suitable solubilizing agents include quaternary ammoniumchlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates.Suitable skin protectants include vitamin E oil, allatoin, dimethicone,glycerin, petrolatum, and zinc oxide.

Transdermal formulations typically employ transdermal delivery devicesand transdermal delivery patches wherein the compound is formulated inlipophilic emulsions or buffered, aqueous solutions, dissolved and/ordispersed in a polymer or an adhesive. Patches may be constructed forcontinuous, pulsatile, or on demand delivery of pharmaceutical agents.Transdermal delivery of the compounds may be accomplished by means of aniontophoretic patch. Transdermal patches may provide controlled deliveryof the compounds wherein the rate of absorption is slowed by usingrate-controlling membranes or by trapping the compound within a polymermatrix or gel. Absorption enhancers may be used to increase absorption,examples of which include absorbable pharmaceutically acceptablesolvents that assist passage through the skin.

Ophthalmic formulations include eye drops.

Formulations for rectal administration include enemas, rectal gels,rectal foams, rectal aerosols, and retention enemas, which may containconventional suppository bases such as cocoa butter or other glycerides,as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and thelike. Compositions for rectal or vaginal administration may also beformulated as suppositories which can be prepared by mixing the compoundwith suitable non-irritating carriers and excipients such as cocoabutter, mixtures of fatty acid glycerides, polyethylene glycol,suppository waxes, and combinations thereof, all of which are solid atambient temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the compound.

Dosage Amounts

As used herein, the term, “therapeutically effective amount” refers toan amount of a compound of the present invention or a pharmaceuticallyacceptable salt or a stereoisomer thereof that is effective in producingthe desired therapeutic response in a particular patient suffering froma disease or disorder characterized or mediated by aberrant activity ofa protein selected from the group consisting of casein kinase 1 alpha(CK1α), family with sequence similarity 83 member F (FAM83F), DTW domaincontaining 1 (DTWD1), zinc finger protein 91 homolog (ZFP91), ZFP62,ZFP36 ring finger protein like (ZFP36L2), ring finger protein 166(RNF166), Ikaros family zinc finger protein 1 (IKZF1), IKZF2, IKZF3,IKZF4, IKZF5, Ras-related protein Rab-28 (RAB28), glutathioneS-transferase pi 1 (GSTP1), GSPT2, mitochondrial import inner membranetranslocase subunit Tim10 (TIMM10), GDNF inducible zinc finger protein 1(GZF1), early growth response 1 (EGR1)-, hypermethylated in cancer 1(HIC1)-, HIC2-, insulinoma-associated protein 2 (INSM2)-, odd-skippedrelated transcription factor 2 (OSR2), protein polybromo-1 (PB1), PRdomain zinc finger protein 15 (PRD15), spalt like transcription factor 1(SALL1), SALL3, SALL4, WIZ, zinc finger and BTB domain-containingprotein 17 (ZBT17), ZBT41, ZBT49, ZBT7A, ZBT7B, ZBTB2, ZBTB39, zincfinger protein interacting with K protein 1 (ZIK1), zinc finger protein3 (ZNF3), ZNF217, ZNF276, ZNF316, ZNF324B, ZNF335, ZNF397, ZNF407,ZNF408, ZNF462, ZNF483, SNF517, ZNF526, ZNF581, ZNF587, ZNF589, ZNF618,ZNF644, ZNF646, ZNF653, ZNF654, ZNF692, ZNF724, ZNF771, ZNF782, ZNF784,ZNF814, zinc finger and SCAN domain containing 10 (ZSC10), ZSC22, ZC827,and zinc finger with UFM1-specific peptidase domain (ZUFSP). In someembodiments, the disease or disorder is characterized or mediated byaberrant activity of IKZF2. The term “therapeutically effective amount”includes the amount of the compound of the present invention or apharmaceutically acceptable salt or a stereoisomer thereof, that whenadministered, induces a positive modification in the disease or disorderto be treated (e.g., remission), or is sufficient to prevent developmentor progression of the disease or disorder, or alleviate to some extent,one or more of the symptoms of the disease or disorder being treated ina subject, or which simply kills or inhibits the growth of diseased(e.g., cancer) cells.

The total daily dosage of the compounds of present invention and usagethereof may be decided in accordance with standard medical practice,e.g., by the attending physician using sound medical judgment. Thespecific therapeutically effective dose for any particular patient willdepend upon a variety of factors including the disease or disorder beingtreated and the severity thereof (e.g., its present status); theactivity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed; and like factors well known in the medical arts (see,for example, Goodman and Gilman's, “The Pharmacological Basis ofTherapeutics”, 10th Edition, A. Gilman, J. Hardman and L. Limbird, eds.,McGraw-Hill Press, 155-173, 2001).

Compounds of the present invention may be effective over a wide dosagerange. In some embodiments, the total daily dosage (e.g., for adulthumans) may range from about 0.001 to about 1600 mg, from 0.01 to about1000 mg, from 0.01 to about 500 mg, from about 0.01 to about 100 mg,from about 0.5 to about 100 mg, from 1 to about 100-400 mg per day, fromabout 1 to about 50 mg per day, and from about 5 to about 40 mg per day,and in yet other embodiments from about 10 to about 30 mg per day.Individual dosage may be formulated to contain the desired dosage amountdepending upon the number of times the compound is administered per day.By way of example, capsules may be formulated with from about 1 to about200 mg of compound (e.g., 1, 2, 2.5, 3, 4, 5, 10, 15, 20, 25, 50, 100,150, and 200 mg). In some embodiments, individual dosages may beformulated to contain the desired dosage amount depending upon thenumber of times the compound is administered per day.

Methods of Use

In some aspects, compounds of the present invention may be useful in thetreatment of diseases and disorders characterized by aberrant activityof a protein that can be targeted for degradation by cereblon,participates in the inception, manifestation of one or more symptoms ormarkers, severity or progression of the disease or disorder, and wherethe degradation of the targeted protein may confer a therapeuticbenefit. The diseases or disorders may be said to be characterized ormediated by aberrant protein activity which as disclosed above, mayinvolve elevated protein levels compared to a non-pathological state. A“disease” is generally regarded as a state of health of an animalwherein the animal cannot maintain homeostasis, and wherein if thedisease is not ameliorated then the animal's health continues todeteriorate. In contrast, a “disorder” in an animal is a state of healthin which the animal is able to maintain homeostasis, but in which theanimal's state of health is less favorable than it would be in theabsence of the disorder. Left untreated, a disorder does not necessarilycause a further decrease in the animal's state of health. In someembodiments, compounds of the application may be useful in the treatmentof proliferative diseases and disorders (e.g., cancer or benignneoplasms). As used herein, the term “cell proliferative disease ordisorder” refers to the conditions characterized by unregulated orabnormal cell growth, or both, including noncancerous conditions,precancerous conditions, and cancer.

The term “subject” (or “patient”) as used herein includes all members ofthe animal kingdom prone to or suffering from the indicated disease ordisorder. In some embodiments, the subject is a mammal, e.g., a human ora non-human mammal. The methods are also applicable to companion animalssuch as dogs and cats as well as livestock such as cows, horses, sheep,goats, pigs, and other domesticated and wild animals. A subject “in needof” treatment according to the present invention may be “suffering fromor suspected of suffering from” a specific disease or disorder may havebeen positively diagnosed or otherwise presents with a sufficient numberof risk factors or a sufficient number or combination of signs orsymptoms such that a medical professional could diagnose or suspect thatthe subject was suffering from the disease or disorder. Thus, subjectssuffering from, and suspected of suffering from, a specific disease ordisorder are not necessarily two distinct groups.

Exemplary types of non-cancerous (e.g., cell proliferative) diseases ordisorders that may be amenable to treatment with the compounds of thepresent invention include inflammatory diseases and conditions,autoimmune diseases, neurodegenerative diseases, heart diseases, viraldiseases, chronic and acute kidney diseases or injuries, metabolicdiseases, allergic and genetic diseases.

Representative examples of specific non-cancerous diseases and disordersinclude rheumatoid arthritis, alopecia areata, lymphoproliferativeconditions, autoimmune hematological disorders (e.g. hemolytic anemia,aplastic anemia, anhidrotic ecodermal dysplasia, pure red cell anemiaand idiopathic thrombocytopenia), cholecystitis, acromegaly, rheumatoidspondylitis, osteoarthritis, gout, scleroderma, sepsis, septic shock,dacryoadenitis, cryopyrin associated periodic syndrome (CAPS), endotoxicshock, endometritis, gram-negative sepsis, keratoconjunctivitis sicca,toxic shock syndrome, asthma, adult respiratory distress syndrome,chronic obstructive pulmonary disease, chronic pulmonary inflammation,chronic graft rejection, hidradenitis suppurativa, inflammatory boweldisease, Crohn's disease, Behcet's syndrome, systemic lupuserythematosus, glomerulonephritis, multiple sclerosis, juvenile-onsetdiabetes, autoimmune uveoretinitis, autoimmune vasculitis, thyroiditis,Addison's disease, lichen planus, appendicitis, bullous pemphigus,pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus,myasthenia gravis, immunoglobulin A nephropathy, autoimmune thyroiditisor Hashimoto's disease, Sjogren's syndrome, vitiligo, Wegenergranulomatosis, granulomatous orchitis, autoimmune oophoritis,sarcoidosis, rheumatic carditis, ankylosing spondylitis, Grave'sdisease, autoimmune thrombocytopenic purpura, psoriasis, psoriaticarthritis, eczema, dermatitis herpetiformis, ulcerative colitis,pancreatic fibrosis, hepatitis, hepatic fibrosis, CD14 mediated sepsis,non-CD14 mediated sepsis, acute and chronic renal disease, irritablebowel syndrome, pyresis, restenosis, cerebral malaria, cervicitis,stroke and ischemic injury, neural trauma, acute and chronic pain,allergic rhinitis, allergic conjunctivitis, chronic heart failure,congestive heart failure, acute coronary syndrome, cachexia, malaria,leprosy, leishmaniasis, Lyme disease, Reiter's syndrome, acutesynovitis, muscle degeneration, bursitis, tendonitis, tenosynovitis,herniated, ruptured, or prolapsed intervertebral disk syndrome,osteopetrosis, rhinosinusitis, thrombosis, silicosis, pulmonarysarcosis, bone resorption diseases, such as osteoporosis,graft-versus-host reaction, fibromyalgia, AIDS and other viral diseasessuch as Herpes Zoster, Herpes Simplex I or II, influenza virus andcytomegalovirus, diabetes Type I and II, obesity, insulin resistance anddiabetic retinopathy, 22q1 1.2 deletion syndrome, Angelman syndrome,Canavan disease, celiac disease, Charcot-Marie-Tooth disease, colorblindness, Cri du chat, Down syndrome, cystic fibrosis, Duchennemuscular dystrophy, haemophilia, Klinefleter's syndrome,neurofibromatosis, phenylketonuria, Prader-Willi syndrome, sudden infantdeath syndrome, sickle cell disease, Tay-Sachs disease, Turner syndrome,urea cycle disorders, thalassemia, otitis, pancreatitis, parotitis,pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,pneumonitis, cystic fibrosis, uveitis, polymyositis, proctitis,interstitial lung fibrosis, dermatomyositis, arteriosclerosis,amyotrophic lateral sclerosis, asocality, immune response, varicosis,vaginitis, including chronic recurrent yeast vaginitis, depression, andSudden Infant Death Syndrome.

In other embodiments, the methods are directed to treating subjectshaving cancer.

Broadly, the compounds of the present invention may be effective in thetreatment of carcinomas (solid tumors including both primary andmetastatic tumors), sarcomas, melanomas, and hematological cancers(cancers affecting blood including lymphocytes, bone marrow and/or lymphnodes) including leukemia, lymphoma and multiple myeloma. Adulttumors/cancers and pediatric tumors/cancers are included. The cancersmay be vascularized, or not yet substantially vascularized, ornon-vascularized tumors.

Representative examples of cancers includes adenocortical carcinoma,AIDS-related cancers (e.g., Kaposi's and AIDS-related lymphoma),appendix cancer, childhood cancers (e.g., childhood cerebellarastrocytoma, childhood cerebral astrocytoma), basal cell carcinoma, skincancer (non-melanoma), biliary cancer, extrahepatic bile duct cancer,intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer,brain cancer (e.g., gliomas and glioblastomas such as brain stem glioma,cerebellar astrocytoma, cerebral astrocytoma/malignant glioma,ependymoma, medulloblastoma, supratentorial primitive neuroectodeimaltumors, visual pathway and hypothalamic glioma), breast cancer,bronchial adenomas/carcinoids, carcinoid tumor, nervous system cancer(e.g., central nervous system cancer, central nervous system lymphoma),cervical cancer, chronic myeloproliferative disorders, colorectal cancer(e.g., colon cancer, rectal cancer), lymphoid neoplasm, mycosisfungoids, Sezary Syndrome, endometrial cancer, esophageal cancer,extracranial germ cell tumor, extragonadal germ cell tumor, extrahepaticbile duct cancer, eye cancer, intraocular melanoma, retinoblastoma,gallbladder cancer, gastrointestinal cancer (e.g., stomach cancer, smallintestine cancer, gastrointestinal carcinoid tumor, gastrointestinalstromal tumor (GIST)), cholangiocarcinoma, germ cell tumor, ovarian germcell tumor, gestational trophoblastic tumor glioma, head and neckcancer, neuroendocrine tumors, Hodgkin's lymphoma, Ann Arbor stage IIIand stage IV childhood Non-Hodgkin's lymphoma, ROS1-positive refractoryNon-Hodgkin's lymphoma, leukemia, lymphoma, multiple myeloma,hypopharyngeal cancer, intraocular melanoma, ocular cancer, islet celltumors (endocrine pancreas), renal cancer (e.g., Wilm's Tumor, renalcell carcinoma), liver cancer, lung cancer (e.g., non-small cell lungcancer and small cell lung cancer), ALK-positive anaplastic large celllymphoma, ALK-positive advanced malignant solid neoplasm, Waldenstrom'smacroglobulinema, melanoma, intraocular (eye) melanoma, merkel cellcarcinoma, mesothelioma, metastatic squamous neck cancer with occultprimary, multiple endocrine neoplasia (MEN), myelodysplastic syndromes,myelodyplastic/myeloproliferative diseases, nasopharyngeal cancer,neuroblastoma, oral cancer (e.g., mouth cancer, lip cancer, oral cavitycancer, tongue cancer, oropharyngeal cancer, throat cancer, laryngealcancer), ovarian cancer (e.g., ovarian epithelial cancer, ovarian germcell tumor, ovarian low malignant potential tumor), pancreatic cancer,islet cell pancreatic cancer, paranasal sinus and nasal cavity cancer,parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma,pineoblastoma, metastatic anaplastic thyroid cancer, undifferentiatedthyroid cancer, papillary thyroid cancer, pituitary tumor, plasma cellneoplasm/multiple myeloma, pleuropulmonary blastoma, prostate cancer,retinoblastoma rhabdomyosarcoma, salivary gland cancer, uterine cancer(e.g., endometrial uterine cancer, uterine sarcoma, uterine corpuscancer), squamous cell carcinoma, testicular cancer, thymoma, thymiccarcinoma, thyroid cancer, juvenile xanthogranuloma, transitional cellcancer of the renal pelvis and ureter and other urinary organs, urethralcancer, gestational trophoblastic tumor, vaginal cancer, vulvar cancer,hepatoblastoma, rhabdoid tumor, and Wilms tumor.

Sarcomas that may be treatable with compounds of the present inventioninclude both soft tissue and bone cancers alike, representative examplesof which include osteosarcoma or osteogenic sarcoma (bone) (e.g.,Ewing's sarcoma), chondrosarcoma (cartilage), leiomyosarcoma (smoothmuscle), rhabdomyosarcoma (skeletal muscle), mesothelial sarcoma ormesothelioma (membranous lining of body cavities), fibrosarcoma (fibroustissue), angiosarcoma or hemangioendothelioma (blood vessels),liposarcoma (adipose tissue), glioma or astrocytoma (neurogenicconnective tissue found in the brain), myxosarcoma (primitive embryonicconnective tissue), mesenchymous or mixed mesodermal tumor (mixedconnective tissue types), and histiocytic sarcoma (immune cancer).

In some embodiments, methods of the present invention entail treatmentof subjects having cell proliferative diseases or disorders of thehematological system, liver (hepatocellular), brain, lung, colorectal(e.g., colon), pancreas, prostate, ovary, breast, skin (e.g., melanoma),and endometrium.

As used herein, “cell proliferative diseases or disorders of thehematologic system” include lymphoma, leukemia, myeloid neoplasms, mastcell neoplasms, myelodysplasia, benign monoclonal gammopathy,lymphomatoid papulosis, polycythemia vera, chronic myelocytic leukemia,agnogenic myeloid metaplasia, and essential thrombocythemia.Representative examples of hematologic cancers may thus include multiplemyeloma, lymphoma (including T-cell lymphoma, Hodgkin's lymphoma,non-Hodgkin's lymphoma (diffuse large B-cell lymphoma (DLBCL),follicular lymphoma (FL), mantle cell lymphoma (MCL) and ALK+ anaplasticlarge cell lymphoma (e.g., B-cell non-Hodgkin's lymphoma selected fromdiffuse large B-cell lymphoma (e.g., germinal center B-cell-like diffuselarge B-cell lymphoma or activated B-cell-like diffuse large B-celllymphoma), Burkitt's lymphoma/leukemia, mantle cell lymphoma,mediastinal (thymic) large B-cell lymphoma, follicular lymphoma,marginal zone lymphoma, lymphoplasmacytic lymphoma/Waldenstrommacroglobulinemia, refractory B-cell non-Hodgkin's lymphoma, andrelapsed B-cell non-Hodgkin's lymphoma, childhood lymphomas, andlymphomas of lymphocytic and cutaneous origin, e.g., small lymphocyticlymphoma, primary CNS lymphoma (PCNSL), marginal zone lymphoma (MZL),leukemia, including chronic lymphocytic leukemia (CLL), childhoodleukemia, hairy-cell leukemia, acute lymphocytic leukemia, acutemyelocytic leukemia, acute myeloid leukemia (e.g., acute monocyticleukemia), chronic lymphocytic leukemia, small lymphocytic leukemia,chronic myelocytic leukemia, chronic myelogenous leukemia, and mast cellleukemia, myeloid neoplasms and mast cell neoplasms.

As used herein, “cell proliferative diseases or disorders of the liver”include all forms of cell proliferative disorders affecting the liver.Cell proliferative disorders of the liver may include liver cancer(e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma andhepatoblastoma), a precancer or precancerous condition of the liver,benign growths or lesions of the liver, and malignant growths or lesionsof the liver, and metastatic lesions in tissue and organs in the bodyother than the liver. Cell proliferative disorders of the brain mayinclude hyperplasia, metaplasia, and dysplasia of the liver.

As used herein, “cell proliferative diseases or disorders of the brain”include all forms of cell proliferative disorders affecting the brain.Cell proliferative disorders of the brain may include brain cancer(e.g., gliomas, glioblastomas, meningiomas, pituitary adenomas,vestibular schwannomas, and primitive neuroectodermal tumors(medulloblastomas)), a precancer or precancerous condition of the brain,benign growths or lesions of the brain, and malignant growths or lesionsof the brain, and metastatic lesions in tissue and organs in the bodyother than the brain. Cell proliferative disorders of the brain mayinclude hyperplasia, metaplasia, and dysplasia of the brain.

As used herein, “cell proliferative diseases or disorders of the lung”include all forms of cell proliferative disorders affecting lung cells.Cell proliferative disorders of the lung include lung cancer, aprecancer or precancerous condition of the lung, benign growths orlesions of the lung, and metastatic lesions in the tissue and organs inthe body other than the lung. Lung cancer includes all forms of cancerof the lung, e.g., malignant lung neoplasms, carcinoma in situ, typicalcarcinoid tumors, and atypical carcinoid tumors. Lung cancer includessmall cell lung cancer (“SLCL”), non-small cell lung cancer (“NSCLC”),squamous cell carcinoma, adenocarcinoma, small cell carcinoma, largecell carcinoma, squamous cell carcinoma, and mesothelioma. Lung cancercan include “scar carcinoma”, bronchioloalveolar carcinoma, giant cellcarcinoma, spindle cell carcinoma, and large cell neuroendocrinecarcinoma. Lung cancer includes lung neoplasms having histologic andultrastructural heterogeneity (e.g., mixed cell types).

As used herein, “cell proliferative diseases or disorders of the colon”include all forms of cell proliferative disorders affecting colon cells,including colon cancer, a precancer or precancerous conditions of thecolon, adenomatous polyps of the colon and metachronous lesions of thecolon. Colon cancer includes sporadic and hereditary colon cancer,malignant colon neoplasms, carcinoma in situ, typical carcinoid tumors,and atypical carcinoid tumors, adenocarcinoma, squamous cell carcinoma,and squamous cell carcinoma. Colon cancer can be associated with ahereditary syndrome such as hereditary nonpolyposis colorectal cancer,familiar adenomatous polyposis, MYH-associated polyposis, Gardner'ssyndrome, Peutz-Jeghers syndrome, Turcot's syndrome and juvenilepolyposis. Cell proliferative disorders of the colon may also becharacterized by hyperplasia, metaplasia, or dysplasia of the colon.

As used herein, “cell proliferative diseases or disorders of thepancreas” include all forms of cell proliferative disorders affectingpancreatic cells. Cell proliferative disorders of the pancreas mayinclude pancreatic cancer, an precancer or precancerous condition of thepancreas, hyperplasia of the pancreas, and dysplasia of the pancreas,benign growths or lesions of the pancreas, and malignant growths orlesions of the pancreas, and metastatic lesions in tissue and organs inthe body other than the pancreas. Pancreatic cancer includes all formsof cancer of the pancreas, including ductal adenocarcinoma,adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinousadenocarcinoma, osteoclast-like giant cell carcinoma, mucinouscystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma,small cell carcinoma, pancreatoblastoma, papillary neoplasm, mucinouscystadenoma, papillary cystic neoplasm, and serous cystadenoma, andpancreatic neoplasms having histologic and ultrastructural heterogeneity(e.g., mixed cell types).

As used herein, “cell proliferative diseases or disorders of theprostate” include all forms of cell proliferative disorders affectingthe prostate. Cell proliferative disorders of the prostate may includeprostate cancer, a precancer or precancerous condition of the prostate,benign growths or lesions of the prostate, and malignant growths orlesions of the prostate, and metastatic lesions in tissue and organs inthe body other than the prostate. Cell proliferative disorders of theprostate may include hyperplasia, metaplasia, and dysplasia of theprostate.

As used herein, “cell proliferative diseases or disorders of the ovary”include all forms of cell proliferative disorders affecting cells of theovary. Cell proliferative disorders of the ovary may include a precanceror precancerous condition of the ovary, benign growths or lesions of theovary, ovarian cancer, and metastatic lesions in tissue and organs inthe body other than the ovary. Cell proliferative disorders of the ovarymay include hyperplasia, metaplasia, and dysplasia of the ovary.

As used herein, “cell proliferative diseases or disorders of the breast”include all forms of cell proliferative disorders affecting breastcells. Cell proliferative disorders of the breast may include breastcancer, a precancer or precancerous condition of the breast, benigngrowths or lesions of the breast, and metastatic lesions in tissue andorgans in the body other than the breast. Cell proliferative disordersof the breast may include hyperplasia, metaplasia, and dysplasia of thebreast.

As used herein, “cell proliferative diseases or disorders of the skin”include all forms of cell proliferative disorders affecting skin cells.Cell proliferative disorders of the skin may include a precancer orprecancerous condition of the skin, benign growths or lesions of theskin, melanoma, malignant melanoma or other malignant growths or lesionsof the skin, and metastatic lesions in tissue and organs in the bodyother than the skin. Cell proliferative disorders of the skin mayinclude hyperplasia, metaplasia, and dysplasia of the skin.

As used herein, “cell proliferative diseases or disorders of theendometrium” include all forms of cell proliferative disorders affectingthe endometrium. Cell proliferative disorders of the endometrium mayinclude endometrial cancer, a precancer or precancerous condition of theendometrium, benign growths or lesions of the endometrium, and malignantgrowths or lesions of the endometrium, and metastatic lesions in tissueand organs in the body other than the endometrium. Cell proliferativedisorders of the endometrium may include hyperplasia, metaplasia, anddysplasia of the endometrium.

The compounds of the present invention may be administered to a patient,e.g., a cancer patient, as a monotherapy or by way of combinationtherapy, and as a front-line therapy or a follow-on therapy for patientswho are unresponsive to front line therapy. Therapy may be “first-line”,i.e., as an initial treatment in patients who have undergone no prioranti-cancer treatment regimens, either alone or in combination withother treatments; or “second-line”, as a treatment in patients who haveundergone a prior anti-cancer treatment regimen, either alone or incombination with other treatments; or as “third-line”, “fourth-line”,etc. treatments, either alone or in combination with other treatments.Therapy may also be given to patients who have had previous treatmentswhich have been partially successful but are intolerant to theparticular treatment. Therapy may also be given as an adjuvanttreatment, i.e., to prevent reoccurrence of cancer in patients with nocurrently detectable disease or after surgical removal of a tumor. Thus,in some embodiments, the compound may be administered to a patient whohas received another therapy, such as chemotherapy, radioimmunotherapy,surgical therapy, immunotherapy, radiation therapy, targeted therapy orany combination thereof.

The methods of the present application may entail administration ofcompounds of the present invention or pharmaceutical compositionsthereof to the patient in a single dose or in multiple doses (e.g., 1,2, 3, 4, 5, 6, 7, 8, 10, 15, 20, or more doses). For example, thefrequency of administration may range from once a day up to about onceevery eight weeks. In some embodiments, the frequency of administrationranges from about once a day for 1, 2, 3, 4, 5 or 6 weeks, and in otherembodiments entails a 28-day cycle which includes daily administrationfor 3 weeks (21 days).

Combination Therapy

Compounds of the present invention may be used in combination with atleast one other active agent, e.g., anti-cancer agent or regimen, intreating diseases and disorders. The term “in combination” in thiscontext means that the agents are co-administered, which includessubstantially contemporaneous administration, by the same or separatedosage forms, or sequentially, e.g., as part of the same treatmentregimen or by way of successive treatment regimens. Thus, if givensequentially, at the onset of administration of the second compound, thefirst of the two compounds is in some cases still detectable ateffective concentrations at the site of treatment. The sequence and timeinterval may be determined such that they can act together (e.g.,synergistically to provide an increased benefit than if they wereadministered otherwise). For example, the therapeutics may beadministered at the same time or sequentially in any order at differentpoints in time; however, if not administered at the same time, they maybe administered sufficiently close in time so as to provide the desiredtherapeutic effect, which may be in a synergistic fashion. Thus, theterms are not limited to the administration of the active agents atexactly the same time.

In some embodiments, the treatment regimen may include administration ofa compound of the present invention in combination with one or moreadditional therapeutics known for use in treating the disease orcondition (e.g., cancer). The dosage of the additional anticancertherapeutic may be the same or even lower than known or recommendeddoses. See, Hardman et al., eds., Goodman & Gilman's The PharmacologicalBasis Of Therapeutics, 10th ed., McGraw-Hill, New York, 2001;Physician's Desk Reference 60th ed., 2006. For example, anti-canceragents that may be used in combination with the inventive compounds areknown in the art. See, e.g., U.S. Pat. No. 9,101,622 (Section 5.2thereof) and U.S. Pat. No. 9,345,705 B2 (Columns 12-18 thereof).Representative examples of additional active agents and treatmentregimens include radiation therapy, chemotherapeutics (e.g., mitoticinhibitors, angiogenesis inhibitors, anti-hormones, autophagyinhibitors, alkylating agents, intercalating antibiotics, growth factorinhibitors, anti-androgens, signal transduction pathway inhibitors,anti-microtubule agents, platinum coordination complexes, HDACinhibitors, proteasome inhibitors, and topoisomerase inhibitors),immunomodulators, therapeutic antibodies (e.g., mono-specific andbispecific antibodies) and CAR-T therapy.

In some embodiments, the compound of the invention and the additional(e.g., anticancer) therapeutic may be administered less than 5 minutesapart, less than 30 minutes apart, less than 1 hour apart, at about 1hour apart, at about 1 to about 2 hours apart, at about 2 hours to about3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hoursto about 5 hours apart, at about 5 hours to about 6 hours apart, atabout 6 hours to about 7 hours apart, at about 7 hours to about 8 hoursapart, at about 8 hours to about 9 hours apart, at about 9 hours toabout 10 hours apart, at about 10 hours to about 11 hours apart, atabout 11 hours to about 12 hours apart, at about 12 hours to 18 hoursapart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hoursto 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hoursapart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hoursto 96 hours apart, or 96 hours to 120 hours part. The two or moreanticancer therapeutics may be administered within the same patientvisit.

In some embodiments, the compound of the present invention and theadditional agent or therapeutic (e.g., an anti-cancer therapeutic) arecyclically administered. Cycling therapy involves the administration ofone anticancer therapeutic for a period of time, followed by theadministration of a second anti-cancer therapeutic for a period of timeand repeating this sequential administration, i.e., the cycle, in orderto reduce the development of resistance to one or both of the anticancertherapeutics, to avoid or reduce the side effects of one or both of theanticancer therapeutics, and/or to improve the efficacy of thetherapies. In one example in the context of cancer treatment, cyclingtherapy involves the administration of a first anticancer therapeuticfor a period of time, followed by the administration of a secondanticancer therapeutic for a period of time, optionally, followed by theadministration of a third anticancer therapeutic for a period of timeand so forth, and repeating this sequential administration, i.e., thecycle in order to reduce the development of resistance to one of theanticancer therapeutics, to avoid or reduce the side effects of one ofthe anticancer therapeutics, and/or to improve the efficacy of theanticancer therapeutics.

Pharmaceutical Kits

The present compositions may be assembled into kits or pharmaceuticalsystems. Kits or pharmaceutical systems according to this aspect of theinvention include a carrier or package such as a box, carton, tube orthe like, having in close confinement therein one or more containers,such as vials, tubes, ampoules, or bottles, which contain a compound ofthe present invention or a pharmaceutical composition thereof. The kitsor pharmaceutical systems of the invention may also include printedinstructions for using the compound and composition.

These and other aspects of the present application will be furtherappreciated upon consideration of the following Examples, which areintended to illustrate certain particular embodiments of the applicationbut are not intended to limit its scope, as defined by the claims.

EXAMPLES Example 1: Synthesis ofN-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-((2-fluorophenyl)amino)pyrimidin-4-yl)amino)acetamide(1)

tert-Butyl(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-2-oxoethyl)-carbamate

To a solution of (tert-butoxycarbonyl)glycine (2.1 g, 12 mmol), DIEA (5mL, 30 mmol) in DMF (30 mL) was added1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU) (4.94 g, 13 mmol), stirred for 0.5 h,and then Lenalidomide (2.59 g, 10 mmol) was added, the mixture was thenstirred at room temperature for another 1 h. The mixture was thenpurified by silica gel (MeOH/DCM=0-10%) to obtain the title compound.

LCMS (m/z): 417 [M+H]⁺.

2-Amino-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide

To a solution of tert-Butyl(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-2-oxoethyl)-carbamatein DCM (30 mL) was added TFA (10 mL), and stirred at room temperaturefor 3 h. The mixture was then concentrated in vacuo, and purified bysilica gel (MeOH/DCM=0-30%) to obtain the title compound (972 mg, 23%for 2 steps).

LCMS (m/z): 317 [M+H]⁺.

2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide

To a solution of2-amino-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide(972 mg, 2.26 mmol) and 2,4-dichloropyrimidine (332 mg, 2.26 mmol) inTHE (20 mL) was added DIEA (1.1 mL, 6.78 mmol), and then stirredovernight. The mixture was then concentrated in vacuo, and purified bysilica gel (MeOH/DCM=0-10%) to obtain the title compound (693 mg, 72%).

LCMS (m/z): 429 [M+H]⁺.

To a solution of2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (50 mg, 0.12 mmol) and 2-fluoroaniline (13 mg, 0.12 mmol) in^(t)BuOH (1 mL) was added TFA (18 μL, 0.24 mmol), and then the mixturewas heated to reflux overnight. The mixture was then concentrated invacuo, and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) to obtaincompound 1 (4.6 mg, 6%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.05 (s, 1H), 10.18 (s, 1H), 10.06 (s, 1H),9.38 (t, J=5.7 Hz, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.83-7.74 (m, 2H),7.57-7.49 (m, 2H), 7.26-7.16 (m, 1H), 7.08-6.97 (m, 1H), 6.45 (d, J=7.2Hz, 1H), 5.16 (dd, J=13.3, 5.2 Hz, 1H), 4.31-4.22 (m, 4H), 2.93 (ddd,J=17.4, 13.6, 5.4 Hz, 1H), 2.65-2.56 (m, 1H), 2.24 (qd, J=13.2, 4.5 Hz,1H), 2.03 (ddd, J=10.3, 5.4, 2.8 Hz, 1H).

LCMS (m/z): 504 [M+H]⁺.

Example 2: Synthesis of2-((2-((2,3-dihydro-1H-inden-5-yl)amino)pyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide(2)

To a solution of2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (50 mg, 0.12 mmol) and 2,3-dihydro-1H-inden-5-amine (16 mg,0.12 mmol) in ^(t)BuOH (1 mL) was added TFA (18 μL, 0.24 mmol), and thenthe mixture was heated to reflux overnight. The mixture was thenconcentrated in vacuo, and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA)to obtain compound 2 (4.4 mg, 6%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.01 (s, 1H), 10.32 (s, 1H), 10.11 (s, 1H),9.30 (t, J=5.9 Hz, 1H), 7.82 (d, J=7.2 Hz, 1H), 7.58-7.48 (m, 2H), 7.34(s, 1H), 7.26-7.18 (m, 2H), 7.08 (d, J=8.0 Hz, 1H), 6.39 (d, J=7.2 Hz,1H), 5.12 (dd, J=13.3, 5.1 Hz, 1H), 4.33-4.25 (m, 4H), 2.85 (dt, J=14.5,7.7 Hz, 2H), 2.73 (q, J=7.5 Hz, 4H), 2.07-1.96 (m, 2H), 1.91 (p, J=7.0Hz, 2H).

LCMS (m/z): 526 [M+H]⁺.

Example 3: Synthesis of2-((2-((benzo[d][1,3]dioxol-5-ylmethyl)amino)pyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide(3)

To a solution of2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (50 mg, 0.12 mmol) and benzo[d][1,3]dioxol-5-ylmethanamine (18mg, 0.12 mmol) in ^(t)BuOH (1 mL) was added TFA (18 μL, 0.24 mmol), andthen the mixture was heated to reflux overnight. The mixture was thenconcentrated in vacuo, and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA)to obtain compound 3 (6.5 mg, 4%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.02 (s, 1H), 9.85 (d, J=4.6 Hz, 1H), 7.78(dd, J=7.6, 1.4 Hz, 1H), 7.68 (d, J=5.7 Hz, 1H), 7.54-7.43 (m, 2H), 7.32(s, 1H), 6.94 (s, 1H), 6.82 (s, 1H), 6.76-6.65 (m, 2H), 5.90 (s, 2H),5.86 (d, J=6.0 Hz, 1H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.36-4.22 (m,4H), 4.09 (d, J=5.9 Hz, 2H), 2.92 (ddd, J=17.2, 13.6, 5.4 Hz, 1H),2.69-2.57 (m, 1H), 2.32-2.18 (m, 1H), 2.03-1.96 (m, 1H).

LCMS (m/z): 544 [M+H]⁺.

Example 4: Synthesis ofN-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)pyrimidin-4-yl)amino)acetamide(4)

To a solution of2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (50 mg, 0.12 mmol) and (S)-pyrrolidin-2-ylmethanol (12 mg,0.12 mmol) in ^(t)BuOH (1 mL) was added TFA (18 μL, 0.24 mmol), and thenthe mixture was heated to reflux overnight. The mixture was thenconcentrated in vacuo, and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA)to obtain compound 4 (1.9 mg, 3%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.88 (s, 1H), 11.04 (s, 1H), 10.13 (s, 1H),9.12 (s, 1H), 7.83 (dd, J=7.6, 1.4 Hz, 1H), 7.73 (d, J=7.3 Hz, 1H),7.57-7.46 (m, 2H), 6.29 (d, J=7.2 Hz, 1H), 5.18 (dd, J=13.3, 5.1 Hz,1H), 4.42-4.26 (m, 4H), 3.64-3.34 (m, 4H), 2.94 (ddd, J=18.1, 13.5, 5.4Hz, 1H), 2.67-2.60 (m, 1H), 2.30 (dd, J=13.1, 4.6 Hz, 1H), 2.10-1.90 (m,6H).

LCMS (m/z): 494 [M+H]⁺.

Example 5: Synthesis of2-((2-(benzo[d][1,3]dioxol-5-ylamino)pyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide(5)

To a solution of2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (60 mg, 0.14 mmol) and 2,3-dihydrobenzo[b][1,4]dioxin-6-amine(21 mg, 0.14 mmol) in ^(t)BuOH (1 mL) was added TFA (21 μL, 0.28 mmol),and then the mixture was heated to reflux overnight. The mixture wasthen concentrated in vacuo, and purified by prep-HPLC (MeOH/H₂O, 0.05%TFA) to obtain compound 5 (5.2 mg, 6%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.02 (s, 1H), 10.25 (s, 1H), 10.12 (s, 1H),9.28 (s, 1H), 7.83-7.74 (m, 2H), 7.56-7.47 (m, 2H), 7.01 (d, J=2.5 Hz,1H), 6.97 (d, J=8.6 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 6.37 (d, J=7.2 Hz,1H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.32 (s, 2H), 4.16-4.05 (m, 4H),2.92 (ddd, J=17.2, 13.5, 5.4 Hz, 1H), 2.64-2.56 (m, 1H), 2.32-2.20 (m,1H), 2.06-1.95 (m, 1H).

LCMS (m/z): 530 [M+H]⁺.

Example 6: Synthesis ofN-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-((3-(2-oxopyrrolidin-1-yl)propyl)amino)pyrimidin-4-yl)amino)acetamide(6)

To a solution of2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (60 mg, 0.14 mmol) and 1 1-(3-aminopropyl)pyrrolidin-2-one (20mg, 0.14 mmol) in ^(t)BuOH (1 mL) was added TFA (18 μL, 0.24 mmol), andthen the mixture was heated to reflux overnight. The mixture was thenconcentrated in vacuo, and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA)to obtain compound 6 (4.1 mg, 5%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.94 (s, 1H), 11.04 (d, J=2.3 Hz, 1H),10.20-10.08 (m, 1H), 8.04-7.93 (m, 1H), 7.85 (ddd, J=17.0, 7.4, 1.6 Hz,1H), 7.74 (d, J=7.3 Hz, 1H), 7.58-7.46 (m, 2H), 6.30-6.23 (m, 1H), 5.17(ddd, J=13.3, 5.2, 2.9 Hz, 1H), 4.49-4.21 (m, 4H), 3.31 (d, J=22.6 Hz,2H), 3.19-3.08 (m, 2H), 2.98-2.90 (m, 1H), 2.67-2.59 (m, 1H), 2.34-2.25(m, 1H), 2.14 (d, J=7.8 Hz, 1H), 2.08-1.99 (m, 1H), 1.81 (s, 1H), 1.62(s, 1H).

LCMS (m/z): 535 [M+H]⁺.

Example 7: Synthesis ofN-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-((4-methoxyphenyl)amino)pyrimidin-4-yl)amino)acetamide(7)

To a solution of2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (100 mg, 0.234 mmol) and 4-methoxyaniline (29 mg, 0.234 mmol)in ^(t)BuOH (1 mL) was added TFA (36 μL, 0.468 mmol), and then themixture was heated to reflux overnight. The mixture was thenconcentrated in vacuo and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) toobtain compound 7 (10.9 mg, 7%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.02 (s, 1H), 10.46 (s, 1H), 10.15 (s, 1H),9.32 (d, J=5.7 Hz, 1H), 7.81 (td, J=9.1, 7.7, 4.1 Hz, 2H), 7.58-7.47 (m,2H), 7.42 (d, J=8.5 Hz, 2H), 6.78 (d, J=8.5 Hz, 2H), 6.38 (d, J=7.2 Hz,1H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.33-4.23 (m, 4H), 3.60 (s, 3H),2.93 (ddd, J=17.2, 13.5, 5.4 Hz, 1H), 2.65-2.56 (m, 1H), 2.23 (qd,J=13.2, 4.4 Hz, 1H), 2.01 (dtd, J=12.4, 7.4, 6.2, 3.7 Hz, 1H).

LCMS (m/z): 516 [M+H]⁺.

Example 8: Synthesis of2-((2-([1,1′-biphenyl]-4-yl)pyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide(8)

To a solution of2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (110 mg, 0.24 mmol) and [1,1′-biphenyl]-4-ylboronic acid (54mg, 0.28 mmol) in ^(t)BuOH (2 mL) were added N,N-Dicyclohexylmethylamine(52 mg, 0.26 mmol), Pd₂dba₃ (22 mg, 0.024 mmol) andTri-tert-butylphosphonium tetrafluoroborate (20 mg, 0.048 mmol). Themixture was heated to 80° C. and stirred under N2 atmosphere overnight.The mixture was then filtered, concentrated in vacuo and purified byprep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain compound 8 (4.4 mg, 3%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.01 (s, 1H), 10.30 (s, 1H), 8.77 (dd,J=4.4, 1.4 Hz, 1H), 8.36 (d, J=8.2 Hz, 2H), 8.31-8.27 (m, 1H), 7.90-7.72(m, 5H), 7.56-7.50 (m, 4H), 7.49-7.39 (m, 1H), 6.88 (d, J=6.7 Hz, 1H),5.11 (dd, J=13.4, 5.0 Hz, 1H), 4.49 (d, J=5.4 Hz, 2H), 4.37 (s, 2H),2.87 (t, J=13.9 Hz, 1H), 2.64 (d, J=5.1 Hz, 1H), 2.17 (d, J=13.4 Hz,1H), 1.96 (s, 1H).

LCMS (m/z): 547 [M+H]⁺.

Example 9: Synthesis ofN-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-(3-methoxyphenyl)pyrimidin-4-yl)amino)acetamide(9)

To a solution of2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (100 mg, 0.23 mmol) and (3-methoxyphenyl)boronic acid (43 mg,0.28 mmol) in ^(t)BuOH (2 mL) were added N,N-Dicyclohexylmethylamine (49mg, 0.25 mmol), Pd₂dba₃ (21 mg, 0.023 mmol) andTri-tert-butylphosphonium tetrafluoroborate (13 mg, 0.046 mmol). Themixture was heated to 80° C. and stirred under N2 atmosphere overnight.The mixture was then filtered, concentrated in vacuo and purified byprep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain compound 9 (4.0 mg, 3%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.03 (s, 1H), 10.31 (s, 1H), 9.79 (s, 1H),8.24 (d, J=7.2 Hz, 1H), 8.19-8.17 (m, 1H), 7.81 (dd, J=7.6, 1.5 Hz, 1H),7.68 (ddd, J=8.9, 7.3, 1.8 Hz, 1H), 7.56-7.52 (m, 2H), 7.32 (d, J=8.4Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 6.98 (d, J=7.2 Hz, 1H), 5.14 (dd,J=13.3, 5.2 Hz, 1H), 4.50 (d, J=5.5 Hz, 2H), 4.36-4.25 (m, 2H), 3.98 (s,3H), 2.92 (ddd, J=18.3, 13.4, 5.5 Hz, 1H), 2.62-2.56 (m, 1H), 2.15-2.07(m, 1H), 2.00-1.96 (m, 1H).

LCMS (m/z): 501 [M+H]⁺.

Example 10: Synthesis of2-((2-(2,5-dimethoxyphenyl)pyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide(10)

To a solution of2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (100 mg, 0.23 mmol) and (2,5-dimethoxyphenyl)boronic acid (51mg, 0.28 mmol) in ^(t)BuOH (2 mL) were added N,N-Dicyclohexylmethylamine(49 mg, 0.25 mmol), Pd₂dba₃ (21 mg, 0.023 mmol) andTri-tert-butylphosphonium tetrafluoroborate (13 mg, 0.046 mmol). Themixture was heated to 80° C. and stirred under N2 atmosphere overnight.The mixture was then filtered, concentrated in vacuo and purified byprep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain compound 10 (2.8 mg, 1%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.01 (s, 1H), 10.30 (s, 1H), 9.60 (s, 1H),8.23 (d, J=9.3 Hz, 1H), 8.16 (d, J=7.2 Hz, 1H), 7.84-7.78 (m, 1H),7.59-7.49 (m, 2H), 6.88 (d, J=7.1 Hz, 1H), 6.80 (d, J=2.4 Hz, 1H), 6.66(dt, J=8.9, 2.0 Hz, 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (d, J=5.5Hz, 2H), 4.32 (s, 2H), 4.01 (s, 3H), 3.89 (s, 3H), 2.92 (ddd, J=18.3,13.5, 5.4 Hz, 1H), 2.58 (d, J=17.5 Hz, 1H), 2.20-2.08 (m, 1H), 2.01-1.90(m, 1H).

LCMS (m/z): 531 [M+H]⁺.

Example 11: Synthesis ofN-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-(4-fluorophenyl)pyrimidin-4-yl)amino)acetamide(11)

To a solution of2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (100 mg, 0.23 mmol) and (4-fluorophenyl)boronic acid (50 mg,0.28 mmol) in ^(t)BuOH (2 mL) were added N,N-Dicyclohexylmethylamine (49mg, 0.25 mmol), Pd₂dba₃ (21 mg, 0.023 mmol) andTri-tert-butylphosphonium tetrafluoroborate (13 mg, 0.046 mmol). Themixture was heated to 80° C. and stirred under N2 atmosphere overnight.The mixture was then filtered, concentrated in vacuo and purified byprep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain compound 11 (10.0 mg, 3%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.02 (s, 1H), 10.30 (s, 1H), 9.30 (s, 1H),8.36-8.23 (m, 2H), 7.81 (d, J=7.2 Hz, 1H), 7.57-7.49 (m, 3H), 7.42 (t,J=8.6 Hz, 2H), 6.88 (d, J=6.8 Hz, 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H),4.47 (d, J=5.3 Hz, 2H), 4.34 (s, 2H), 2.92 (ddt, J=18.1, 13.6, 4.7 Hz,1H), 2.65-2.57 (m, 1H), 2.19-2.12 (m, 1H), 1.98 (d, J=10.2 Hz, 1H).

LCMS (m/z): 489 [M+H]⁺.

Example 12: Synthesis of2-((2-(4-acetylphenyl)pyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide(12)

To a solution of2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (100 mg, 0.23 mmol) and (4-acetylphenyl)boronic acid (45 mg,0.28 mmol) in ^(t)BuOH (2 mL) were added N,N-Dicyclohexylmethylamine (49mg, 0.25 mmol), Pd₂dba₃ (21 mg, 0.023 mmol) andTri-tert-butylphosphonium tetrafluoroborate (13 mg, 0.046 mmol). Themixture was heated to 80° C. and stirred under N2 atmosphere overnight.The mixture was then filtered, concentrated in vacuo and purified byprep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain 12 (3.6 mg, 3%).

¹H NMR (500 MHz, DMSO-d₆) δ 10.99 (s, 1H), 10.22 (s, 1H), 8.75 (s, 1H),8.40 (d, J=8.4 Hz, 2H), 8.29 (d, J=6.4 Hz, 1H), 8.06 (d, J=8.1 Hz, 2H),7.81 (d, J=7.4 Hz, 1H), 7.57-7.47 (m, 2H), 6.82 (d, J=6.4 Hz, 1H), 5.11(dd, J=13.1, 5.1 Hz, 1H), 4.43-4.38 (m, 2H), 4.33 (s, 2H), 2.90 (ddd,J=18.2, 13.5, 5.4 Hz, 1H), 2.63 (s, 3H), 2.57 (d, J=19.1 Hz, 1H), 2.14(d, J=13.6 Hz, 1H), 2.00-1.91 (m, 1H).

LCMS (m/z): 513 [M+H]⁺.

Example 13: Synthesis of2-((2-(benzofuran-2-yl)pyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide(13)

To a solution of2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (150 mg, 0.35 mmol) and benzofuran-2-ylboronic acid (68 mg,0.42 mmol) in ^(t)BuOH (2 mL) were added N,N-Dicyclohexylmethylamine (75mg, 0.39 mmol), Pd₂dba₃ (32 mg, 0.035 mmol) andTri-tert-butylphosphonium tetrafluoroborate (20 mg, 0.07 mmol). Themixture was heated to 80° C. and stirred under N2 atmosphere overnight.The mixture was then filtered, concentrated in vacuo and purified byprep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain 13 (12.3 mg, 6%).

¹H NMR (500 MHz, DMSO-d₆) δ 10.99 (s, 1H), 10.20 (s, 1H), 8.22 (d, J=5.8Hz, 1H), 8.14 (s, 1H), 7.83 (dd, J=7.4, 1.6 Hz, 1H), 7.72 (d, J=7.8 Hz,1H), 7.66 (s, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.56-7.49 (m, 2H), 7.43-7.38(m, 1H), 7.29 (s, 1H), 6.67 (s, 1H), 5.07 (dd, J=13.4, 4.9 Hz, 1H), 4.36(d, J=22.3 Hz, 4H), 2.92-2.79 (m, 1H), 2.46 (s, 1H), 2.13 (d, J=13.9 Hz,1H), 1.89 (s, 1H).

LCMS (m/z): 511 [M+H]⁺.

Example 14: Synthesis ofN-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)pyrimidin-4-yl)amino)acetamide(14)

To a solution of2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (210 mg, 0.5 mmol) and (R)-pyrrolidin-2-ylmethanol (50 mg, 0.5mmol) in ^(t)BuOH (2 mL) was added TFA (76 μL, 1.0 mmol), and then themixture was heated to reflux overnight. The mixture was thenconcentrated in vacuo and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) toobtain compound 14 (5.1 mg, 2%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.04 (s, 1H), 10.15 (s, 1H), 9.13 (s, 1H),7.83 (d, J=7.6 Hz, 1H), 7.74 (d, J=7.2 Hz, 1H), 7.60-7.47 (m, 2H), 6.29(d, J=7.2 Hz, 1H), 5.18 (dd, J=13.3, 5.2 Hz, 1H), 4.44-4.27 (m, 4H),3.60-3.36 (m, 5H), 2.94 (ddd, J=18.1, 13.5, 5.5 Hz, 1H), 2.68-2.58 (m,1H), 2.30 (tt, J=13.1, 6.7 Hz, 1H), 2.06-2.00 (m, 1H), 1.91 (dqd,J=18.5, 12.4, 6.4 Hz, 4H).

LCMS (m/z): 494 [M+H]⁺.

Example 15: Synthesis ofN-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-((2-methoxyphenyl)amino)pyrimidin-4-yl)amino)acetamide(15)

To a solution of2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (140 mg, 0.33 mmol) and 2-methoxyaniline (40 mg, 0.33 mmol) in^(t)BuOH (2 mL) was added TFA (50 μL, 0.66 mmol), and then the mixturewas heated to reflux overnight. The mixture was then concentrated invacuo and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain compound15 (9.5 mg, 5%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.03 (s, 1H), 10.18 (s, 1H), 9.64 (s, 1H),9.38 (t, J=5.8 Hz, 1H), 7.94-7.77 (m, 3H), 7.56-7.49 (m, 2H), 7.12 (t,J=7.7 Hz, 1H), 7.09-7.07 (m, 1H), 6.80 (t, J=7.7 Hz, 1H), 5.14 (dd,J=13.3, 5.2 Hz, 1H), 4.34-4.20 (m, 4H), 3.83 (s, 3H), 2.92 (ddd, J=17.2,13.5, 5.4 Hz, 1H), 2.66-2.54 (m, 1H), 2.19 (qd, J=13.1, 4.4 Hz, 1H),2.00 (dtd, J=12.8, 5.4, 2.2 Hz, 1H).

LCMS (m/z): 516 [M+H]⁺.

Example 16: Synthesis ofN-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)pyrimidin-4-yl)amino)acetamide(16)

To a solution of2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (135 mg, 0.316 mmol) and1-(3-(trifluoromethyl)phenyl)piperazine (73 mg, 0.316 mmol) in ^(t)BuOH(2 mL) was added TFA (48 μL, 0.632 mmol), and then the mixture washeated to reflux overnight. The mixture was then concentrated in vacuoand purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain compound 16(12.1 mg, 5%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.04 (s, 1H), 10.27 (s, 1H), 9.27 (t, J=5.6Hz, 1H), 7.88 (dd, J=7.4, 1.6 Hz, 1H), 7.80 (dd, J=7.2, 2.1 Hz, 1H),7.59-7.51 (m, 2H), 7.47-7.43 (m, 1H), 7.29-7.22 (m, 1H), 7.17 (t, J=6.9Hz, 1H), 7.11 (d, J=7.5 Hz, 1H), 5.18 (dd, J=13.3, 5.1 Hz, 1H), 4.36(dd, J=34.4, 7.4 Hz, 4H), 3.85 (t, J=5.1 Hz, 4H), 3.37 (dt, J=48.5, 5.2Hz, 4H), 2.93 (ddd, J=18.0, 13.5, 5.3 Hz, 1H), 2.64-2.57 (m, 1H), 2.31(qd, J=13.2, 4.4 Hz, 1H), 2.04 (ddd, J=13.3, 5.8, 3.4 Hz, 1H).

LCMS (m/z): 623 [M+H]⁺.

Example 17: Synthesis ofN-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-(methyl(phenyl)amino)pyrimidin-4-yl)amino)acetamide(17)

To a solution of2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (135 mg, 0.316 mmol) and N-methylaniline (34 mg, 0.316 mmol)in ^(t)BuOH (2 mL) was added TFA (48 μL, 0.632 mmol), and then themixture was heated to reflux overnight. The mixture was thenconcentrated in and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) toobtain compound 17 (16.5 mg, 6%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.04 (s, 1H), 10.20 (s, 1H), 9.35 (t, J=5.7Hz, 1H), 7.86 (dd, J=7.4, 1.6 Hz, 1H), 7.60 (d, J=7.2 Hz, 1H), 7.57-7.53(m, 2H), 7.49 (d, J=7.4 Hz, 2H), 7.45 (dt, J=8.2, 2.6 Hz, 3H), 6.38 (d,J=7.2 Hz, 1H), 5.18 (dd, J=13.3, 5.1 Hz, 1H), 4.46-4.28 (m, 4H), 3.44(s, 3H), 2.99-2.87 (m, 1H), 2.67-2.58 (m, 1H), 2.31 (qd, J=13.2, 4.5 Hz,1H), 2.13-1.96 (m, 1H).

LCMS (m/z): 500 [M+H]⁺.

Example 18: Synthesis of2-((2-(benzyl(ethyl)amino)pyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide(25)

To a solution of2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (98 mg, 0.23 mmol) and N-benzylethanamine (31 mg, 0.23 mmol)in ^(t)BuOH (2 mL) was added TFA (36 μL, 0.46 mmol), and then themixture was heated to reflux overnight. The mixture was thenconcentrated in vacuo and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) toobtain compound 25 (1.4 mg, 0.8%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.04 (s, 1H), 10.05 (s, 1H), 7.77 (dt,J=13.2, 7.1 Hz, 2H), 7.54-7.46 (m, 2H), 7.40-7.18 (m, 6H), 6.33 (d,J=6.6 Hz, 1H), 5.15 (dd, J=13.2, 5.2 Hz, 1H), 4.78 (d, J=16.6 Hz, 2H),4.30 (d, J=5.7 Hz, 4H), 3.52 (s, 2H), 2.93 (ddd, J=17.4, 13.6, 5.4 Hz,1H), 2.68-2.57 (m, 1H), 2.17 (d, J=16.2 Hz, 1H), 2.01 (s, 1H), 1.03 (t,J=7.0 Hz, 3H).

LCMS (m/z): 528 [M+H]⁺.

Example 19: Synthesis ofN-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-((2-(4-fluoro-2-methoxyphenyl)pyrimidin-4-yl)amino)acetamide(34)

To a solution of2-((2-chloropyrimidin-4-yl)amino)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide (100 mg, 0.23 mmol) and (4-fluoro-2-methoxyphenyl)boronic acid(60 mg, 0.28 mmol) in ^(t)BuOH (2 mL) were addedN,N-Dicyclohexylmethylamine (49 mg, 0.25 mmol), Pd₂dba₃ (21 mg, 0.023mmol) and Tri-tert-butylphosphonium tetrafluoroborate (13 mg, 0.046mmol). The mixture was heated to 80° C. and stirred under N2 atmosphereovernight. The mixture was then filtered, concentrated in vacuo andpurified by prep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain compound 34 (1.6mg, 1%).

LCMS (m/z): 519 [M+H]⁺.

Examples 20: Synthesis of3-(4-((2-((4-methoxyphenyl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(18)

3-(4-((2-Chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution of Lenalidomide (777 mg, 3 mmol) and2,4-dichloropyrimidine (882 mg, 6 mmol) in DMF (6 mL) was added DIEA(1.5 mL, 9 mmol), and then the mixture was heated to 110° C. overnight.The mixture was concentrated in vacuo and then purified by silica gel(MeOH/DCM=0-6%) to obtain the title compound (321 mg, 29%) as a palewhite solid.

LCMS (m/z): 372 [M+H]⁺.

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(112 mg, 0.3 mmol) and 4-methoxyaniline (37 mg, 0.3 mmol) in ^(t)BuOH (2mL) was added TFA (45 μL, 0.6 mmol), and then the mixture was heated toreflux overnight. The mixture was then concentrated in vacuo andpurified by prep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain compound 18 (64.3mg, 38%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.01 (s, 1H), 10.36 (d, J=51.4 Hz, 2H),7.94 (dd, J=41.2, 7.4 Hz, 2H), 7.65 (d, J=7.5 Hz, 1H), 7.56 (t, J=7.7Hz, 1H), 7.32 (d, J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 6.43 (d, J=6.9Hz, 1H), 5.14 (dd, J=13.2, 5.2 Hz, 1H), 4.46 (d, J=17.5 Hz, 1H), 4.33(d, J=17.4 Hz, 1H), 3.74 (s, 3H), 2.90 (ddd, J=18.1, 13.6, 5.4 Hz, 1H),2.62-2.53 (m, 1H), 2.35-2.24 (m, 1H), 1.87 (d, J=11.2 Hz, 1H).

LCMS (m/z): 459 [M+H]⁺.

Example 21: Synthesis of3-(4-((2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(19)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(98 mg, 0.26 mmol) and 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (40 mg,0.26 mmol) in ^(t)BuOH (2 mL) was added TFA (40 μL, 0.52 mmol), and thenthe mixture was heated to reflux overnight. The mixture was thenconcentrated in vacuo and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) toobtain compound 19 (15.9 mg, 10.1%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.01 (s, 1H), 10.41 (d, J=52.9 Hz, 2H),7.94 (dd, J=57.8, 7.2 Hz, 2H), 7.69-7.49 (m, 2H), 6.99 (s, 1H),6.85-6.71 (m, 2H), 6.43 (d, J=6.9 Hz, 1H), 5.14 (dd, J=13.3, 5.3 Hz,1H), 4.46 (d, J=17.5 Hz, 1H), 4.30 (d, J=17.4 Hz, 1H), 4.20 (s, 4H),2.97-2.85 (m, 1H), 2.57 (s, 1H), 2.25 (s, 1H), 1.82 (s, 1H).

LCMS (m/z): 487 [M+H]⁺.

Example 22: Synthesis of3-(4-((2-((2-fluorophenyl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(21)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(83 mg, 0.22 mmol) and 2-fluoroaniline (25 mg, 0.22 mmol) in ^(t)BuOH (2mL) was added TFA (33 μL, 0.44 mmol), and then the mixture was heated toreflux overnight. The mixture was then concentrated in vacuo andpurified by prep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain compound 21 (11.0mg, 9%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.02 (s, 1H), 10.31 (s, 1H), 10.01 (s, 1H),8.07 (d, J=6.8 Hz, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.59 (dd, J=9.9, 7.0 Hz,2H), 7.46 (t, J=7.7 Hz, 1H), 7.30 (ddd, J=10.5, 8.3, 1.4 Hz, 1H), 7.24(tdd, J=7.9, 5.2, 1.6 Hz, 1H), 7.11 (t, J=7.7 Hz, 1H), 6.49 (d, J=6.7Hz, 1H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.45 (d, J=17.5 Hz, 1H), 4.33(d, J=17.4 Hz, 1H), 2.96-2.84 (m, 1H), 2.59 (dt, J=17.0, 3.3 Hz, 1H),2.31 (qd, J=13.2, 4.4 Hz, 1H), 1.97-1.84 (m, 1H). LCMS (m/z): 447[M+H]⁺.

Example 23: Synthesis of3-(1-oxo-4-((2-((3-(2-oxopyrrolidin-1-yl)propyl)amino)pyrimidin-4-yl)amino)isoindolin-2-yl)piperidine-2,6-dione(22)

To a solution of of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(90 mg, 0.24 mmol) and 1-(3-aminopropyl)pyrrolidin-2-one (34 mg, 0.24mmol) in ^(t)BuOH (2 mL) was added TFA (36 μL, 0.48 mmol), and then themixture was heated to reflux overnight. The mixture was thenconcentrated in vacuo and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) toobtain compound 22 (8.6 mg, 6%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.03 (s, 1H), 10.58 (s, 1H), 8.32 (s, 1H),7.93 (d, J=6.9 Hz, 2H), 7.65 (dd, J=18.8, 7.5 Hz, 2H), 6.38 (s, 1H),5.19 (dd, J=13.3, 5.1 Hz, 1H), 4.48 (d, J=17.7 Hz, 1H), 4.38 (d, J=17.8Hz, 1H), 3.17 (d, J=21.2 Hz, 6H), 2.94 (ddd, J=18.0, 13.7, 5.4 Hz, 1H),2.60 (d, J=17.2 Hz, 1H), 2.39 (qd, J=13.2, 4.5 Hz, 1H), 2.14 (s, 2H),2.02 (d, J=12.2 Hz, 1H), 1.73 (d, J=83.3 Hz, 4H).

LCMS (m/z): 478 [M+H]⁺.

Example 24: Synthesis of3-(1-oxo-4-((2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)pyrimidin-4-yl)amino)isoindolin-2-yl)piperidine-2,6-dione(23)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(85 mg, 0.23 mmol) and 1-(3-(trifluoromethyl)phenyl)piperazine (53 mg,0.23 mmol) in ^(t)BuOH (2 mL) was added TFA (35 μL, 0.46 mmol), and thenthe mixture was heated to reflux overnight. The mixture was thenconcentrated in vacuo and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) toobtain compound 23 (10.9 mg, 7%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.03 (s, 1H), 10.53 (s, 1H), 8.00 (d, J=6.9Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.4 Hz, 1H), 7.62 (t, J=7.7Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.28-7.23 (m, 1H), 7.22 (t, J=1.9 Hz,1H), 7.10 (d, J=7.6 Hz, 1H), 6.41 (d, J=6.9 Hz, 1H), 5.19 (dd, J=13.3,5.2 Hz, 1H), 4.47 (d, J=17.6 Hz, 1H), 4.37 (d, J=17.5 Hz, 1H), 3.76 (q,J=4.0 Hz, 4H), 3.39 (t, J=4.3 Hz, 4H), 2.93 (ddd, J=17.4, 13.7, 5.4 Hz,1H), 2.58 (dt, J=17.2, 3.1 Hz, 1H), 2.38 (qd, J=13.2, 4.4 Hz, 1H), 2.02(ddq, J=10.5, 5.6, 3.3, 2.7 Hz, 1H).

LCMS (m/z): 566 [M+H]⁺.

Example 25: Synthesis of3-(4-((2-((2,3-dihydro-1H-inden-5-yl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(24)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(90 mg, 0.24 mmol) and 2,3-dihydro-1H-inden-5-amine (33 mg, 0.24 mmol)in ^(t)BuOH (2 mL) was added TFA (36 μL, 0.48 mmol), and then themixture was heated to reflux overnight. The mixture was thenconcentrated in vacuo and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) toobtain compound 24 (15.6 mg, 11%).

¹H NMR (500 MHz, DMSO-d₆) δ 10.99 (s, 1H), 10.47 (d, J=32.6 Hz, 2H),8.03 (d, J=6.9 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.68 (d, J=7.4 Hz, 1H),7.58 (t, J=7.7 Hz, 1H), 7.32 (s, 1H), 7.09 (q, J=8.2 Hz, 2H), 6.45 (d,J=6.9 Hz, 1H), 5.12 (dd, J=13.3, 5.1 Hz, 1H), 4.46 (d, J=17.5 Hz, 1H),4.31 (d, J=17.5 Hz, 1H), 2.88 (ddd, J=18.0, 13.6, 5.4 Hz, 1H), 2.79 (t,J=7.4 Hz, 2H), 2.68 (t, J=6.8 Hz, 2H), 2.57-2.55 (m, 1H), 2.22 (qd,J=13.3, 4.4 Hz, 1H), 1.98 (p, J=7.4 Hz, 2H), 1.75 (d, J=12.2 Hz, 1H).

LCMS (m/z): 469 [M+H]⁺.

Example 26: Synthesis of3-(4-((2-(benzyl(ethyl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(26)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(90 mg, 0.24 mmol) and N-benzylethanamine (33 mg, 0.24 mmol) in ^(t)BuOH(2 mL) was added TFA (36 μL, 0.48 mmol), and then the mixture was heatedto reflux overnight. The mixture was then concentrated in vacuo andpurified by prep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain compound 26 (7.6mg, 5%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.04 (s, 1H), 10.38 (s, 1H), 7.96 (d, J=7.0Hz, 1H), 7.64-7.55 (m, 1H), 7.38-7.24 (m, 4H), 7.18 (s, 2H), 6.43 (s,1H), 5.17 (dd, J=13.3, 5.1 Hz, 1H), 4.74 (s, 2H), 4.50-4.28 (m, 2H),3.55 (s, 2H), 2.93 (ddd, J=17.3, 13.6, 5.4 Hz, 1H), 2.61 (dt, J=17.2,3.3 Hz, 1H), 2.36 (qd, J=12.9, 4.4 Hz, 1H), 2.07-1.93 (m, 1H), 1.10 (s,3H).

LCMS (m/z): 471 [M+H]⁺.

Example 27: Synthesis of3-(4-((2-(methyl(phenyl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(27)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(80 mg, 0.22 mmol) and N-methylaniline (23 mg, 0.22 mmol) in ^(t)BuOH (2mL) was added TFA (33 μL, 0.44 mmol), and then the mixture was heated toreflux overnight. The mixture was then concentrated in vacuo andpurified by prep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain compound 27 (17.4mg, 14%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.05 (s, 1H), 10.50 (s, 1H), 7.86 (dd,J=22.4, 7.5 Hz, 2H), 7.58 (d, J=7.5 Hz, 1H), 7.53 (t, J=7.6 Hz, 2H),7.47-7.39 (m, 4H), 6.50 (d, J=7.0 Hz, 1H), 5.18 (dd, J=13.3, 5.1 Hz,1H), 4.47 (d, J=17.5 Hz, 1H), 4.37 (d, J=17.5 Hz, 1H), 3.39 (s, 3H),2.94 (ddd, J=17.3, 13.6, 5.4 Hz, 1H), 2.62 (dt, J=17.2, 3.4 Hz, 1H),2.37 (qd, J=13.2, 4.4 Hz, 1H), 2.02 (dtd, J=12.8, 5.3, 2.3 Hz, 1H).

LCMS (m/z): 443 [M+H]⁺.

Example 28: Synthesis of3-(4-((2-(mesitylamino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(28)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(86 mg, 0.23 mmol) and 2,4,6-trimethylaniline (31 mg, 0.23 mmol) in^(t)BuOH (2 mL) was added TFA (35 μL, 0.46 mmol), and then the mixturewas heated to reflux overnight. The mixture was then concentrated invacuo and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain compound28 (4.7 mg, 4%).

LCMS (m/z): 471 [M+H]⁺.

Example 29: Synthesis of3-(4-((2-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(29)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(82 mg, 0.22 mmol) and (S)-pyrrolidin-2-ylmethanol (23 mg, 0.22 mmol) in^(t)BuOH (2 mL) was added TFA (33 μL, 0.44 mmol), and then the mixturewas heated to reflux overnight. The mixture was then concentrated invacuo and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain 29 (6.3mg, 5%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.03 (s, 1H), 10.46 (s, 2H), 8.12-7.87 (m,2H), 7.63 (dd, J=20.9, 7.6 Hz, 2H), 6.44 (s, 1H), 5.19 (dt, J=13.3, 5.2Hz, 1H), 4.57-4.31 (m, 2H), 4.11 (s, 1H), 3.47 (d, J=38.9 Hz, 4H), 2.94(ddd, J=18.2, 13.9, 5.0 Hz, 1H), 2.66-2.56 (m, 1H), 2.40-2.31 (m, 1H),2.09 (s, 1H), 2.05-1.84 (m, 4H).

LCMS (m/z): 437 [M+H]⁺.

Example 30: Synthesis of3-(4-((2-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(30)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(82 mg, 0.22 mmol) and (R)-pyrrolidin-2-ylmethanol (23 mg, 0.22 mmol) in^(t)BuOH (2 mL) was added TFA (33 μL, 0.44 mmol), and then the mixturewas heated to reflux overnight. The mixture was then concentrated invacuo and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain compound30 (12.0 mg, 10%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.03 (s, 1H), 10.49 (s, 1H), 8.22-7.88 (m,2H), 7.74-7.37 (m, 2H), 6.44 (s, 1H), 5.18 (dt, J=13.3, 5.2 Hz, 1H),4.56-4.28 (m, 2H), 4.11 (s, 1H), 3.63-3.37 (m, 4H), 2.99-2.85 (m, 1H),2.67-2.56 (m, 1H), 2.43-2.32 (m, 1H), 2.11 (d, J=15.7 Hz, 1H), 2.06-1.83(m, 5H).

LCMS (m/z): 437 [M+H]⁺.

Example 31: Synthesis of3-(4-((2-(((R)-1-hydroxy-3-methylbutan-2-yl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(37)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(100 mg, 0.27 mmol) and (R)-2-amino-3-methylbutan-1-ol (28 mg, 0.27mmol) in ^(t)BuOH (2 mL) was added TFA (41 μL, 0.54 mmol), and then themixture was heated to reflux overnight. The mixture was thenconcentrated in vacuo and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) toobtain compound 37 (4.5 mg, 3%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.02 (s, 1H), 10.50 (s, 1H), 8.21 (s, 1H),7.94 (d, J=7.3 Hz, 2H), 7.66 (d, J=7.1 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H),6.37 (s, 1H), 5.17 (dd, J=13.1, 5.1 Hz, 1H), 4.59-4.34 (m, 2H), 3.48 (d,J=9.0 Hz, 2H), 2.99-2.87 (m, 1H), 2.62 (dd, J=15.3, 11.7 Hz, 1H),2.44-2.31 (m, 1H), 2.01 (d, J=16.2 Hz, 1H), 1.84 (s, 1H), 0.86 (d,J=42.6 Hz, 6H).

LCMS (m/z): 439 [M+H]⁺.

Example 32: Synthesis of3-(4-((2-((2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(38)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(100 mg, 0.27 mmol) and 2-methoxyaniline (33 mg, 0.27 mmol) in ^(t)BuOH(2 mL) was added TFA (41 μL, 0.54 mmol), and then the mixture was heatedto reflux overnight. The mixture was then concentrated in vacuo andpurified by prep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain compound 38 (20.6mg, 13%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.02 (s, 1H), 10.64 (s, 1H), 9.86-9.75 (m,1H), 8.04 (d, J=7.0 Hz, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.65 (dd, J=7.5,0.9 Hz, 1H), 7.53 (t, J=7.6 Hz, 2H), 7.20 (t, J=7.6 Hz, 1H), 7.11 (dd,J=8.4, 1.4 Hz, 1H), 6.82 (t, J=7.8 Hz, 1H), 6.51 (d, J=7.1 Hz, 1H), 5.14(dd, J=13.2, 5.2 Hz, 1H), 4.47 (d, J=17.5 Hz, 1H), 4.34 (d, J=17.5 Hz,1H), 3.82 (s, 3H), 2.90 (ddd, J=17.3, 13.7, 5.4 Hz, 1H), 2.57 (dt,J=17.2, 3.4 Hz, 1H), 2.28 (qd, J=13.2, 4.4 Hz, 1H), 1.87 (d, J=12.6 Hz,1H).

LCMS (m/z): 459 [M+H]⁺.

Example 33: Synthesis of4-((4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pyrimidin-2-yl)amino)benzenesulfonamide(40)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(60 mg, 0.16 mmol) and 4-aminobenzenesulfonamide (28 mg, 0.16 mmol) in^(t)BuOH (2 mL) was added TFA (24 μL, 0.32 mmol), and then the mixturewas heated to reflux overnight. The mixture was then concentrated invacuo and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain compound40 (9.0 mg, 9%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.01 (s, 1H), 10.39 (s, 1H), 10.17 (s, 1H),8.12 (d, J=6.5 Hz, 1H), 7.97 (d, J=7.7 Hz, 1H), 7.72-7.55 (m, 6H), 7.24(s, 2H), 6.48 (d, J=6.6 Hz, 1H), 5.15 (dd, J=13.3, 5.2 Hz, 1H), 4.48 (d,J=17.5 Hz, 1H), 4.37 (d, J=17.5 Hz, 1H), 2.90 (ddd, J=17.3, 13.6, 5.4Hz, 1H), 2.56 (dt, J=16.9, 3.4 Hz, 1H), 2.30 (qd, J=13.2, 4.5 Hz, 1H),1.90 (dtd, J=12.9, 5.4, 2.3 Hz, 1H).

LCMS (m/z): 508 [M+H]⁺.

Example 34: Synthesis of3-(4-((2-(indolin-5-ylamino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(43)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(50 mg, 0.135 mmol) and tert-butyl 5-aminoindoline-1-carboxylate (32 mg,0.135 mmol) in ^(t)BuOH (2 mL) was added TFA (21 μL, 0.27 mmol), andthen the mixture was heated to reflux overnight. The mixture was thenconcentrated in vacuo and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) toobtain compound 43 (10.4 mg, 13%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.01 (s, 1H), 10.48 (d, J=30.2 Hz, 2H),8.02 (d, J=6.9 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.66 (dd, J=7.5, 1.1 Hz,1H), 7.61 (t, J=7.6 Hz, 1H), 7.07 (s, 1H), 7.01 (s, 2H), 6.46 (d, J=6.9Hz, 1H), 5.15 (dd, J=13.2, 5.1 Hz, 1H), 4.49 (d, J=17.5 Hz, 1H), 4.34(d, J=17.5 Hz, 1H), 3.56 (t, J=8.2 Hz, 2H), 2.99 (t, J=8.1 Hz, 2H),2.94-2.85 (m, 1H), 2.64-2.55 (m, 1H), 2.33 (ddd, J=26.6, 13.2, 3.2 Hz,1H), 2.25 (s, 1H), 1.90 (dd, J=11.1, 5.2 Hz, 1H).

LCMS (m/z): 470 [M+H]⁺.

Example 35: Synthesis of3-(4-((2-(((3s,5s,7s)-adamantan-1-yl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(44)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(50 mg, 0.135 mmol) and (3s,5s,7s)-adamantan-1-amine (24 mg, 0.162 mmol)in ^(t)BuOH (2 mL) was added TFA (67 μL, 0.405 mmol), and then themixture was heated to reflux overnight. The mixture was thenconcentrated in vacuo and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) toobtain compound 44 (4.1 mg, 3%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.01 (s, 1H), 10.61 (s, 1H), 7.99 (s, 1H),7.93 (d, J=7.2 Hz, 1H), 7.72 (dd, J=10.6, 7.6 Hz, 2H), 7.62 (t, J=7.6Hz, 1H), 6.33 (d, J=7.2 Hz, 1H), 5.16 (dd, J=13.3, 5.2 Hz, 1H), 4.40 (d,J=17.6 Hz, 1H), 4.30 (d, J=17.6 Hz, 1H), 2.92 (ddd, J=17.3, 13.6, 5.4Hz, 1H), 2.64-2.53 (m, 1H), 2.44-2.36 (m, 1H), 2.09 (s, 1H), 1.96-1.91(m, 1H), 1.86 (s, 3H), 1.76 (s, 6H), 1.50 (d, J=12.2 Hz, 3H), 1.33 (d,J=11.9 Hz, 3H).

LCMS (m/z): 487 [M+H]⁺.

Example 36: Synthesis of3-(4-((2-(naphthalen-2-ylamino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(45)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(50 mg, 0.135 mmol) and tert-butyl 5-aminoindoline-1-carboxylate (23 mg,0.162 mmol) in ^(t)BuOH (2 mL) was added TFA (21 μL, 0.27 mmol), andthen the mixture was heated to reflux overnight. The mixture was thenconcentrated in vacuo and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) toobtain compound 45 (16.8 mg, 21%).

¹H NMR (500 MHz, DMSO-d₆) δ 10.98 (s, 1H), 10.79 (s, 1H), 10.61 (s, 1H),8.11 (d, J=7.0 Hz, 1H), 8.03-8.00 (m, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.84(t, J=8.3 Hz, 2H), 7.71 (d, J=7.5 Hz, 1H), 7.58 (d, J=7.7 Hz, 1H),7.55-7.39 (m, 4H), 6.52 (d, J=6.9 Hz, 1H), 5.08 (dd, J=13.2, 5.2 Hz,1H), 4.49 (d, J=17.6 Hz, 1H), 4.35 (d, J=17.6 Hz, 1H), 2.81 (ddd,J=17.2, 13.7, 5.4 Hz, 1H), 2.45 (s, 1H), 2.16 (dt, J=11.5, 5.3 Hz, 1H),1.62 (s, 1H).

LCMS (m/z): 479 [M+H]⁺.

Example 37: Synthesis of3-(4-((2-((9H-fluoren-3-yl)amino)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(46)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(50 mg, 0.135 mmol) and 9H-fluoren-3-amine (24 mg, 0.135 mmol) in^(t)BuOH (2 mL) was added TFA (21 μL, 0.27 mmol), and then the mixturewas heated to reflux overnight. The mixture was then concentrated andpurified by prep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain compound 46 (30.0mg, 37%).

¹H NMR (500 MHz, DMSO-d₆) δ 10.99 (s, 1H), 10.79 (s, 1H), 10.64 (s, 1H),8.10 (d, J=6.9 Hz, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.82 (d, J=7.5 Hz, 1H),7.79-7.74 (m, 1H), 7.74-7.70 (m, 2H), 7.63 (t, J=7.7 Hz, 1H), 7.55 (d,J=7.4 Hz, 1H), 7.39-7.33 (m, 2H), 7.28 (td, J=7.4, 1.2 Hz, 1H), 6.50 (d,J=7.0 Hz, 1H), 5.12 (dd, J=13.2, 5.2 Hz, 1H), 4.51 (d, J=17.6 Hz, 1H),4.36 (d, J=17.5 Hz, 1H), 2.85 (ddd, J=17.3, 13.6, 5.4 Hz, 1H), 2.54 (d,J=11.7 Hz, 1H), 2.30-2.15 (m, 1H), 1.80-1.67 (m, 1H).

LCMS (m/z): 517 [M+H]⁺.

Example 38: Synthesis of3-(1-oxo-4-((2-((5,6,7,8-tetrahydronaphthalen-2-yl)amino)pyrimidin-4-yl)amino)isoindolin-2-yl)piperidine-2,6-dione(52)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(100 mg, 0.27 mmol) and 5,6,7,8-tetrahydronaphthalen-2-amine (40 mg,0.27 mmol) in ^(t)BuOH (2 mL) was added TFA (41 μL, 0.54 mmol), and thenthe mixture was heated to reflux overnight. The mixture was thenconcentrated in vacuo and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) toobtain compound 52 (70.4 mg, 44%).

¹H NMR (500 MHz, DMSO-d₆) δ 10.99 (s, 1H), 10.62 (s, 1H), 10.54 (s, 1H),8.03 (d, J=7.0 Hz, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H),7.58 (t, J=7.7 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 7.04 (dd, J=8.3, 2.2 Hz,1H), 6.93 (d, J=8.3 Hz, 1H), 6.46 (d, J=7.0 Hz, 1H), 5.12 (dd, J=13.2,5.2 Hz, 1H), 4.45 (d, J=17.6 Hz, 1H), 4.29 (d, J=17.5 Hz, 1H), 2.89(ddd, J=17.3, 13.7, 5.4 Hz, 1H), 2.64 (d, J=6.2 Hz, 2H), 2.55 (d, J=2.6Hz, 1H), 2.45 (s, 2H), 2.20 (qd, J=13.4, 4.3 Hz, 1H), 1.68 (dd, J=7.6,4.3 Hz, 4H). LCMS (m/z): 483 [M+H]⁺.

Example 39: Synthesis of3-(4-((2-(4-acetylphenyl)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(20)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(115 mg, 0.3 mmol) and (4-acetylphenyl)boronic acid (61 mg, 0.36 mmol)in ^(t)BuOH (2 mL) were added N,N-dicyclohexylmethylamine (64 mg, 0.33mmol), Pd₂dba₃ (27 mg, 0.03 mmol) and Tri-tert-butylphosphoniumtetrafluoroborate (18 mg, 0.06 mmol). The mixture was heated to 80° C.and stirred under N2 atmosphere overnight. The mixture was thenfiltered, concentrated in vacuo and purified by prep-HPLC (MeOH/H₂O,0.05% TFA) to obtain compound 20 (10.0 mg, 6%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.00 (s, 1H), 9.65 (s, 1H), 8.49 (d, J=5.8Hz, 1H), 8.37 (d, J=8.3 Hz, 2H), 8.13 (d, J=7.8 Hz, 1H), 8.07 (d, J=8.3Hz, 2H), 7.67-7.53 (m, 2H), 6.87 (d, J=5.9 Hz, 1H), 5.17 (dd, J=13.3,5.1 Hz, 1H), 4.52 (d, J=17.3 Hz, 1H), 4.43 (d, J=17.3 Hz, 1H), 2.92(ddd, J=17.2, 13.6, 5.4 Hz, 1H), 2.63 (s, 3H), 2.61-2.55 (m, 1H), 2.35(qd, J=13.2, 4.4 Hz, 1H), 2.01 (dtd, J=12.7, 5.3, 2.2 Hz, 1H).

LCMS (m/z): 456 [M+H]⁺.

Example 40: Synthesis of3-(4-((2-([1,1′-biphenyl]-4-yl)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(31)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(100 mg, 0.27 mmol) and [1,1′-biphenyl]-4-ylboronic acid (80 mg, 0.41mmol) in ^(t)BuOH (2 mL) were added N,N-Dicyclohexylmethylamine (58 mg,0.30 mmol), Pd₂dba₃ (25 mg, 0.027 mmol) and Tri-tert-butylphosphoniumtetrafluoroborate (16 mg, 0.054 mmol). The mixture was heated to 80° C.and stirred under N2 atmosphere overnight. The mixture was thenfiltered, concentrated in vacuo and purified by prep-HPLC (MeOH/H₂O,0.05% TFA) to obtain compound 31 (4.0 mg, 2%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.01 (s, 1H), 9.99 (s, 1H), 8.47 (d, J=6.1Hz, 1H), 8.30 (d, J=8.5 Hz, 2H), 8.10 (dd, J=7.3, 1.6 Hz, 1H), 7.85 (d,J=8.5 Hz, 2H), 7.79-7.75 (m, 2H), 7.67-7.61 (m, 2H), 7.51 (dd, J=8.4,7.0 Hz, 2H), 7.44-7.39 (m, 1H), 6.88 (d, J=6.2 Hz, 1H), 5.18 (dd,J=13.4, 5.1 Hz, 1H), 4.54 (d, J=17.4 Hz, 1H), 4.44 (d, J=17.4 Hz, 1H),2.92 (ddd, J=18.0, 13.6, 5.4 Hz, 1H), 2.64-2.54 (m, 1H), 2.35 (qd,J=13.2, 4.5 Hz, 1H), 2.07-1.96 (m, 1H).

LCMS (m/z): 490 [M+H]⁺.

Example 41: Synthesis of3-(4-((2-(3-methoxyphenyl)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(32)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(78 mg, 0.21 mmol) and (3-methoxyphenyl)boronic acid (48 mg, 0.32 mmol)in ^(t)BuOH (2 mL) were added N,N-Dicyclohexylmethylamine (45 mg, 0.23mmol), Pd₂dba₃ (19 mg, 0.021 mmol) and Tri-tert-butylphosphoniumtetrafluoroborate (12 mg, 0.042 mmol). The mixture was heated to 80° C.and stirred under N2 atmosphere overnight. The mixture was thenfiltered, concentrated in vacuo and purified by prep-HPLC (MeOH/H₂O,0.05% TFA) to obtain compound 32 (13.7 mg, 12%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.19 (s, 1H), 11.02 (s, 1H), 8.44 (d, J=7.1Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.73 (dd,J=7.5, 1.1 Hz, 1H), 7.67 (td, J=7.8, 7.3, 1.3 Hz, 2H), 7.32 (dd, J=8.5,0.9 Hz, 1H), 7.17 (td, J=7.5, 1.0 Hz, 1H), 7.06 (d, J=6.9 Hz, 1H), 5.18(dd, J=13.3, 5.1 Hz, 1H), 4.52 (d, J=17.6 Hz, 1H), 4.42 (d, J=17.6 Hz,1H), 3.98 (s, 3H), 2.93 (ddd, J=17.3, 13.7, 5.4 Hz, 1H), 2.64-2.55 (m,1H), 2.38-2.29 (m, 1H), 2.00 (ddq, J=10.3, 5.4, 3.1, 2.6 Hz, 1H).

LCMS (m/z): 444 [M+H]⁺.

Example 42: Synthesis of3-(4-((2-(4-fluoro-2-methoxyphenyl)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(33)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(96 mg, 0.26 mmol) and (4-fluoro-2-methoxyphenyl)boronic acid (66 mg,0.39 mmol) in ^(t)BuOH (2 mL) were added N,N-Dicyclohexylmethylamine (56mg, 0.29 mmol), Pd₂dba₃ (22 mg, 0.026 mmol) andTri-tert-butylphosphonium tetrafluoroborate (15 mg, 0.052 mmol). Themixture was heated to 80° C. and stirred under N2 atmosphere overnight.The mixture was then filtered, concentrated in vacuo and purified byprep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain compound 33 (17.1 mg, 11%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.14 (s, 1H), 11.03 (s, 1H), 8.43 (d, J=7.0Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.89 (dd, J=8.8, 6.7 Hz, 1H), 7.72 (dd,J=7.6, 1.0 Hz, 1H), 7.66 (t, J=7.7 Hz, 1H), 7.26 (dd, J=11.3, 2.4 Hz,1H), 7.03 (td, J=8.5, 4.1 Hz, 2H), 5.18 (dd, J=13.3, 5.1 Hz, 1H), 4.50(d, J=17.6 Hz, 1H), 4.41 (d, J=17.6 Hz, 1H), 3.98 (s, 3H), 2.93 (ddd,J=17.3, 13.6, 5.4 Hz, 1H), 2.64-2.56 (m, 1H), 2.33 (qd, J=13.2, 4.4 Hz,1H), 2.00 (dtd, J=12.6, 5.1, 2.1 Hz, 1H).

LCMS (m/z): 462 [M+H]⁺.

Example 43: Synthesis of3-(4-((2-(2,4-dimethoxyphenyl)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(35)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(100 mg, 0.27 mmol) and (2,4-dimethoxyphenyl)boronic acid (74 mg, 0.41mmol) in ^(t)BuOH (2 mL) were added N,N-Dicyclohexylmethylamine (58 mg,0.30 mmol), Pd₂dba₃ (25 mg, 0.027 mmol) and Tri-tert-butylphosphoniumtetrafluoroborate (16 mg, 0.054 mmol). The mixture was heated to 80° C.and stirred under N2 atmosphere overnight. The mixture was thenfiltered, concentrated in vacuo and purified by prep-HPLC (MeOH/H₂O,0.05% TFA) to obtain compound 35 (9.3 mg, 6%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.11 (s, 1H), 11.02 (s, 1H), 8.35 (d, J=7.1Hz, 1H), 7.93 (d, J=8.5 Hz, 2H), 7.74 (d, J=7.5 Hz, 1H), 7.68 (t, J=7.7Hz, 1H), 6.99 (s, 1H), 6.82 (d, J=2.3 Hz, 1H), 6.80-6.76 (m, 1H), 5.18(dd, J=13.3, 5.1 Hz, 1H), 4.51 (d, J=17.6 Hz, 1H), 4.40 (d, J=17.6 Hz,1H), 4.03 (s, 3H), 3.89 (s, 3H), 2.92 (ddd, J=17.3, 13.6, 5.4 Hz, 1H),2.63-2.55 (m, 1H), 2.33 (qd, J=12.9, 4.2 Hz, 1H), 2.00 (td, J=6.0, 2.3Hz, 1H).

LCMS (m/z): 474 [M+H]⁺.

Example 44: Synthesis of3-(4-((2-(benzofuran-2-yl)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(36)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(100 mg, 0.27 mmol) and benzofuran-2-ylboronic acid (65 mg, 0.41 mmol)in ^(t)BuOH (2 mL) were added N,N-Dicyclohexylmethylamine (58 mg, 0.30mmol), Pd₂dba₃ (25 mg, 0.027 mmol) and Tri-tert-butylphosphoniumtetrafluoroborate (16 mg, 0.054 mmol). The mixture was heated to 80° C.and stirred under N2 atmosphere overnight. The mixture was thenfiltered, concentrated in vacuo and purified by prep-HPLC (MeOH/H₂O,0.05% TFA) to obtain compound 36 (5.0 mg, 3%).

¹H NMR (500 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.75 (s, 1H), 8.44 (d, J=5.9Hz, 1H), 8.08 (d, J=7.7 Hz, 1H), 7.78 (dt, J=7.8, 1.0 Hz, 1H), 7.68 (dq,J=8.3, 0.9 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.61-7.57 (m, 2H), 7.43(ddd, J=8.4, 7.2, 1.4 Hz, 1H), 7.34-7.30 (m, 1H), 6.83 (d, J=6.0 Hz,1H), 5.16 (dd, J=13.2, 5.1 Hz, 1H), 4.60 (d, J=17.4 Hz, 1H), 4.44 (d,J=17.4 Hz, 1H), 2.90 (ddd, J=17.3, 13.6, 5.4 Hz, 1H), 2.59-2.53 (m, 1H),2.37 (ddd, J=15.6, 12.4, 4.5 Hz, 1H), 2.03 (ddq, J=10.6, 5.6, 3.3, 2.7Hz, 1H).

LCMS (m/z): 454 [M+H]⁺.

Example 45: Synthesis of3-(4-((2-(4-fluorophenyl)pyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(39)

To a solution of3-(4-((2-chloropyrimidin-4-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(60 mg, 0.16 mmol) and (4-fluorophenyl)boronic acid (34 mg, 0.24 mmol)in BuOH (2 mL) were added N,N-Dicyclohexylmethylamine (34 mg, 0.18mmol), Pd₂dba₃ (15 mg, 0.016 mmol) and Tri-tert-butylphosphoniumtetrafluoroborate (10 mg, 0.032 mmol). The mixture was heated to 80° C.and stirred under N2 atmosphere overnight. The mixture was thenfiltered, concentrated in vacuo and purified by prep-HPLC (MeOH/H₂O,0.05% TFA) to obtain compound 39 (1.5 mg, 2%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.01 (s, 1H), 9.96 (s, 1H), 8.44 (d, J=6.1Hz, 1H), 8.25 (dd, J=8.6, 5.7 Hz, 1H), 8.04 (dd, J=7.0, 1.9 Hz, 1H),7.84 (dd, J=8.3, 6.3 Hz, 1H), 7.62 (d, J=7.0 Hz, 2H), 7.36 (t, J=8.7 Hz,1H), 7.15 (t, J=8.9 Hz, 1H), 6.86 (d, J=6.1 Hz, 1H), 5.17 (dd, J=13.3,5.1 Hz, 1H), 4.50 (d, J=17.4 Hz, 1H), 4.42 (d, J=17.4 Hz, 1H), 2.92(ddd, J=18.2, 13.5, 5.4 Hz, 1H), 2.66-2.55 (m, 1H), 2.34 (qd, J=13.3,4.6 Hz, 1H), 2.03-1.97 (m, 1H).

LCMS (m/z): 432 [M+H]⁺.

Example 46: Synthesis of3-(4-((2-((2,3-dihydro-1H-inden-5-yl)amino)-9-isopropyl-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(53)

3-(4-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution of Lenalidomide (78 mg, 0.34 mmol) and2,6-dichloro-9-isopropyl-9H-purine (88 mg, 0.34 mmol) in DMF (2 mL) wasadded DIEA (169 μL, 1.02 mmol), and then the mixture was heated to 100°C. overnight. The mixture was then concentrated in vacuo and purified byprep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain the title compound.

LCMS (m/z): 454 [M+H]⁺.

To a solution of3-(4-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(60 mg, 0.13 mmol) and 2,3-dihydro-1H-inden-5-amine (18 mg, 0.13 mmol)in ^(t)BuOH (1 mL) was added TFA (20 μL, 0.26 mmol), and then themixture was heated to reflux overnight. The mixture was thenconcentrated in vacuo and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) toobtain compound 53 (19.8 mg, 23%).

¹H NMR (500 MHz, DMSO-d₆) δ 10.93 (s, 1H), 9.74 (s, 1H), 9.03 (s, 1H),8.31 (s, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.69-7.50 (m, 3H), 7.28 (d, J=8.3Hz, 1H), 6.96 (d, J=8.2 Hz, 1H), 5.08 (dd, J=13.2, 5.2 Hz, 1H),4.78-4.68 (m, 1H), 4.57 (d, J=17.3 Hz, 1H), 4.34 (d, J=17.3 Hz, 1H),2.85 (ddd, J=18.3, 13.6, 5.4 Hz, 1H), 2.74 (t, J=7.3 Hz, 2H), 2.64 (t,J=7.5 Hz, 2H), 2.48 (s, 1H), 2.20 (dd, J=13.3, 4.5 Hz, 1H), 1.98-1.88(m, 2H), 1.74-1.67 (m, 1H), 1.57 (d, J=6.7 Hz, 6H).

LCMS (m/z): 551 [M+H]⁺.

Example 47: Synthesis of3-(4-((9-isopropyl-2-((5,6,7,8-tetrahydronaphthalen-2-yl)amino)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(55)

To a solution of3-(4-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(45 mg, 0.1 mmol) and 5,6,7,8-tetrahydronaphthalen-2-amine (15 mg, 0.1mmol) in ^(t)BuOH (1 mL) was added TFA (15 μL, 0.2 mmol), and then themixture was heated to reflux overnight. The mixture was thenconcentrated in vacuo and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) toobtain compound 55 (11.0 mg, 16%).

¹H NMR (500 MHz, DMSO-d₆) δ 10.94 (s, 1H), 9.82 (s, 1H), 9.01 (s, 1H),8.40 (s, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.63-7.50 (m, 2H), 7.41 (s, 1H),7.26 (dd, J=8.3, 2.3 Hz, 1H), 6.80 (d, J=8.3 Hz, 1H), 5.08 (dd, J=13.2,5.1 Hz, 1H), 4.71 (p, J=6.8 Hz, 1H), 4.59 (d, J=17.3 Hz, 1H), 4.35 (d,J=17.3 Hz, 1H), 3.08 (qd, J=7.3, 4.7 Hz, 4H), 2.91-2.81 (m, 1H),2.56-2.52 (m, 1H), 1.77 (d, J=12.2 Hz, 1H), 1.68 (t, J=3.3 Hz, 4H), 1.58(d, J=6.7 Hz, 6H).

LCMS (m/z): 565 [M+H]⁺.

Example 48: Synthesis of3-(4-((9-isopropyl-2-(mesitylamino)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(56)

To a solution of3-(4-((2-chloro-9-isopropyl-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(45 mg, 0.1 mmol) and 2,4,6-trimethylaniline (14 mg, 0.1 mmol) in^(t)BuOH (1 mL) was added TFA (15 μL, 0.2 mmol), and then the mixturewas heated to reflux overnight. The mixture was then concentrated invacuo and purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) to obtain compound56 (0.5 mg, 0.8%).

LCMS (m/z): 553 [M+H]⁺.

Example 49: Synthesis of3-(4-((2-(2-methoxyphenyl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(47)

2,6-Dichloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine

To a solution of 2,6-dichloro-9H-purine (1.89 g, 10 mmol) and NaOH (1.2g, 30 mmol) in DMF (30 mL) was added 2-(Trimethylsilyl)ethoxymethylchloride (3.5 mL, 20 mmol), and then the mixture was stirred for 4 h.The mixture was then extracted with EtOAc, washed with brine, dried overNa₂SO₄, and concentrated in vacuo to the next step without anypurification.

LCMS (m/z): 319 [M+H]⁺.

3-(4-((2-Chloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution of2,6-dichloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine (10 mmol)and lenalidomide (2.6 g, 10 mmol) in DMF (30 mL) was added DIEA (3.3 mL,20 mmol), and then heated up to 110° C., stirred overnight. The mixturewas purified by silica gel (MeOH/DCM=0-4%) directly to provide the titlecompound (1.0 g, 19% for 2 steps) as a yellow solid.

LCMS (m/z): 542 [M+H]⁺.

To a solution of3-(4-((2-chloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(83 mg, 0.15 mmol) and (2-methoxyphenyl)boronic acid (27 mg, 0.18 mmol)in ^(t)BuOH (2 mL) were added N,N-Dicyclohexylmethylamine (32 mg, 0.17mmol), Pd₂dba₃ (14 mg, 0.015 mmol) and Tri-tert-butylphosphoniumtetrafluoroborate (9 mg, 0.03 mmol). The mixture was heated to 80° C.and stirred under N2 atmosphere overnight. The mixture was thenfiltered, concentrated in vacuo and purified by silica gel(MeOH/DCM=0-4%) to provide the intermediate. The intermediate was thenconcentrated in vacuo, dissolved in TFA/DCM=1/1, stirred for 2 h, andthen concentrated again in vacuo, purified by prep-HPLC (MeOH/H₂O, 0.05%TFA) to provide compound 47 (26.0 mg, 29%).

¹H NMR (500 MHz, DMSO-d₆) δ 10.99 (s, 1H), 8.50 (s, 1H), 8.05 (dd,J=6.9, 2.1 Hz, 1H), 7.62-7.50 (m, 4H), 7.45 (ddd, J=8.9, 7.5, 1.8 Hz,1H), 7.17-7.12 (m, 1H), 7.04 (td, J=7.5, 0.9 Hz, 1H), 5.15 (dd, J=13.3,5.1 Hz, 1H), 4.60 (d, J=17.5 Hz, 1H), 4.45 (d, J=17.4 Hz, 1H), 2.92(ddd, J=17.2, 13.6, 5.4 Hz, 1H), 2.60 (d, J=3.3 Hz, 1H), 2.55 (s, 3H),2.32 (qd, J=13.3, 4.6 Hz, 1H), 1.95 (dt, J=10.0, 4.0 Hz, 1H). LCMS(m/z): 484 [M+H]⁺.

Example 50: Synthesis of3-(4-((2-([1,1′-biphenyl]-4-yl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(48)

To a solution of3-(4-((2-chloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(72 mg, 0.13 mmol) and [1,1′-biphenyl]-4-ylboronic acid (32 mg, 0.16mmol) in ^(t)BuOH (2 mL) were added N,N-Dicyclohexylmethylamine (27 mg,0.14 mmol), Pd₂dba₃ (12 mg, 0.013 mmol) and Tri-tert-butylphosphoniumtetrafluoroborate (8 mg, 0.026 mmol). The mixture was heated to 80° C.and stirred under N2 atmosphere overnight. The mixture was thenfiltered, concentrated in vacuo and purified by silica gel(MeOH/DCM=0-4%) to provide the intermediate. The intermediate was thenconcentrated in vacuo, dissolved in TFA/DCM=1/1, stirred for 2 h, andthen concentrated again, purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) toprovide compound 48 (1.7 mg, 2%).

¹H NMR (500 MHz, DMSO-d₆) δ 10.94 (s, 1H), 9.91 (s, 1H), 8.36-8.24 (m,3H), 8.01-7.96 (m, 1H), 7.75 (dd, J=9.9, 7.9 Hz, 4H), 7.64-7.59 (m, 2H),7.49 (dd, J=8.3, 7.1 Hz, 2H), 7.42-7.35 (m, 1H), 5.13 (dd, J=13.1, 5.1Hz, 1H), 4.64 (d, J=17.4 Hz, 1H), 4.51 (d, J=17.4 Hz, 1H), 2.93-2.78 (m,1H), 2.51 (d, J=1.9 Hz, 1H), 2.34 (qd, J=13.2, 4.8 Hz, 1H), 1.96 (dd,J=14.9, 8.4 Hz, 1H).

LCMS (m/z): 530 [M+H]⁺.

Example 51: Synthesis of3-(4-((2-(4-fluoro-2-methoxyphenyl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(49)

To a solution of3-(4-((2-chloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(82 mg, 0.15 mmol) and (4-fluoro-2-methoxyphenyl)boronic acid (31 mg,0.18 mmol) in ^(t)BuOH (2 mL) were added N,N-Dicyclohexylmethylamine (32mg, 0.17 mmol), Pd₂dba₃ (14 mg, 0.015 mmol) andTri-tert-butylphosphonium tetrafluoroborate (9 mg, 0.03 mmol). Themixture was heated to 80° C. and stirred under N2 atmosphere overnight.The mixture was then filtered, concentrated in vacuo and purified bysilica gel (MeOH/DCM=0-4%) to provide the intermediate. The intermediatewas then concentrated in vacuo, dissolved in TFA/DCM=1/1, stirred for 2h, and then concentrated again, purified by prep-HPLC (MeOH/H₂O, 0.05%TFA) to provide compound 49 (16.4 mg, 18%).

¹H NMR (500 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.74 (s, 1H), 8.30 (s, 1H),8.11-7.99 (m, 1H), 7.58-7.48 (m, 3H), 6.98 (dd, J=11.6, 2.4 Hz, 1H),6.82 (td, J=8.4, 2.4 Hz, 1H), 5.13 (dd, J=13.3, 5.1 Hz, 1H), 4.59 (d,J=17.4 Hz, 1H), 4.45 (d, J=17.3 Hz, 1H), 3.77 (s, 3H), 2.91 (ddd,J=17.9, 13.5, 5.4 Hz, 1H), 2.63-2.55 (m, 1H), 2.36 (qd, J=13.2, 4.5 Hz,1H), 1.94 (d, J=12.8 Hz, 1H).

LCMS (m/z): 502 [M+H]⁺.

Example 52: Synthesis of3-(4-((2-(4-fluorophenyl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(50)

To a solution of3-(4-((2-chloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(82 mg, 0.15 mmol) and (4-fluorophenyl)boronic acid (25 mg, 0.18 mmol)in ^(t)BuOH (2 mL) were added N,N-Dicyclohexylmethylamine (32 mg, 0.17mmol), Pd₂dba₃ (14 mg, 0.015 mmol) and Tri-tert-butylphosphoniumtetrafluoroborate (9 mg, 0.03 mmol). The mixture was heated to 80° C.and stirred under N2 atmosphere overnight. The mixture was thenfiltered, concentrated in vacuo and purified by silica gel(MeOH/DCM=0-4%) to provide the intermediate. The intermediate was thenconcentrated in vacuo, dissolved in TFA/DCM=1/1, stirred for 2 h, andthen concentrated again, purified by prep-HPLC (MeOH/H₂O, 0.05% TFA) toprovide compound 50 (6.3 mg, 7%).

¹H NMR (500 MHz, DMSO-d₆) δ 10.94 (s, 1H), 9.89 (s, 1H), 8.34 (s, 1H),8.27-8.20 (m, 2H), 7.95 (dd, J=6.0, 2.9 Hz, 1H), 7.61 (q, J=3.9, 3.1 Hz,2H), 7.31-7.19 (m, 2H), 5.13 (dd, J=13.2, 5.1 Hz, 1H), 4.58 (d, J=17.4Hz, 1H), 4.48 (d, J=17.3 Hz, 1H), 2.88 (ddd, J=18.0, 11.5, 5.4 Hz, 1H),2.55 (s, 1H), 2.33 (qd, J=13.1, 4.4 Hz, 1H), 2.01-1.91 (m, 1H).

LCMS (m/z): 472 [M+H]⁺.

Example 53: Synthesis of3-(4-((2-(3,5-dimethoxyphenyl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(51)

To a solution of3-(4-((2-chloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(90 mg, 0.17 mmol) and (3,5-dimethoxyphenyl)boronic acid (36 mg, 0.2mmol) in ^(t)BuOH (2 mL) were added N,N-Dicyclohexylmethylamine (36 mg,0.18 mmol), Pd₂dba₃ (15 mg, 0.017 mmol) and Tri-tert-butylphosphoniumtetrafluoroborate (10 mg, 0.03 mmol). The mixture was heated to 80° C.and stirred under N2 atmosphere overnight. The mixture was thenfiltered, concentrated in vacuo and purified by silica gel(MeOH/DCM=0-4%) to provide the intermediate. The intermediate was thenconcentrated in vacuo, dissolved in TFA/DCM=1/1, stirred for 2 h, andthen concentrated again in vacuo, purified by prep-HPLC (MeOH/H₂O, 0.05%TFA) to provide compound 51 (4.5 mg, 4%).

LCMS (m/z): 514 [M+H]⁺.

Example 54: Synthesis of4-(3-((2-((2,3-dihydro-1H-inden-5-yl)amino)pyrimidin-4-yl)amino)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(57)

4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of 4-bromoisobenzofuran-1,3-dione (2.27 g, 10 mml) and3-aminopiperidine-2,6-dione hydrochloride (1.8 g, 11 mmol) in AcOH (30mL) was added NaOAc (984 mg, 12 mmol), then the mixture was heated toreflux at 140° C. overnight. The mixture was allowed to cool down, thenthe mixture was filtered, washed with water, and then dried over air toprovide the crude product without any purification.

LCMS (m/z): 337 [M+H]⁺.

tert-Butyl(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1-yl)carbamate

To a solution of4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (336 mg, 1mmol) and tert-butyl prop-2-yn-1-ylcarbamate (310 mg, 2 mmol) in DMF (5mL) were added CuI (38 mg, 0.2 mmol), Et₃N (2.5 mL) and Pd(PPh₃)₂Cl₂ (70mg, 0.1 mmol). The resulting mixture was then heated up to 70° C. andstirred under N2 atmosphere for 3 h. The mixture was then filtered,concentrated in vacuo, and purified by silica gel (MeOH/DCM=0-4%) toobtain the title compound.

LCMS (m/z): 412 [M+H]⁺.

tert-Butyl(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)carbamate

To a solution of tert-butyl(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1-yl)carbamatein MeOH was added Pd/C (10 wt. % loading, matrix carbon), then themixture was hydrogenated at room temperature overnight. The reactionmixture was filtered and the filtrate was concentrated in vacuo toprovide the title compound.

LCMS (m/z): 415 [M+H]⁺.

4-(3-Aminopropyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

A solution of tert-butyl(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)carbamatein TFA/DCM=1/2 (v/v) was stirred at room temperature for 3 h, and thenconcentrated in vacuo. The crude title compound was used in the nextstep without any purification.

LCMS (m/z): 315 [M+H]⁺.

4-(3-((2-chloropyrimidin-4-yl)amino)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of4-(3-aminopropyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione and2,4-dichloropyrimidine (1 eq) in isopropanol was added DIEA (3 eq), andthen the mixture was stirred at 50° C. for 3 h. The mixture was thenconcentrated in vacuo, purified by silica gel (MeOH/DCM=0-10%) toprovide the title compound (115 mg).

LCMS (m/z): 428 [M+H]⁺.

To a solution of4-(3-((2-chloropyrimidin-4-yl)amino)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(50 mg, 0.12 mmol) and 2,3-dihydro-1H-inden-5-amine (16 mg, 0.12 mmol)in ^(t)BuOH (2 mL) was added TFA (18 μL, 0.24 mmol), then the mixturewas stirred at 100° C. overnight. The mixture was concentrated in vacuoand purified by prep-HPLC to provide compound 57 (13.3 mg, 17%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.12 (s, 1H), 10.42 (s, 1H), 9.05 (t, J=5.6Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.79-7.65 (m, 3H), 7.39 (s, 1H),7.27-7.15 (m, 2H), 6.19 (d, J=7.2 Hz, 1H), 5.14 (dd, J=12.9, 5.4 Hz,1H), 3.39 (q, J=6.4 Hz, 2H), 2.94-2.88 (m, 1H), 2.84 (qd, J=7.4, 2.8 Hz,8H), 2.65-2.56 (m, 1H), 1.99 (dq, J=29.1, 7.4 Hz, 6H).

LCMS (m/z): 525 [M+H]⁺.

Example 56: Synthesis of2-(2,6-dioxopiperidin-3-yl)-4-(3-((2-(mesitylamino)pyrimidin-4-yl)amino)propyl)isoindoline-1,3-dione(58)

To a solution of4-(3-((2-chloropyrimidin-4-yl)amino)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(50 mg, 0.12 mmol) and 2,4,6-trimethylaniline (16 mg, 0.12 mmol) in^(t)BuOH (2 mL) was added TFA (18 μL, 0.24 mmol), then the mixture wasstirred at 100° C. overnight. The mixture was concentrated and purifiedby prep-HPLC to provide compound 58 (6.3 mg, 8%).

LCMS (m/z): 527 [M+H]⁺.

Example 57: Synthesis of4-(6-((2-((2,3-dihydro-1H-inden-5-yl)amino)pyrimidin-4-yl)amino)hexyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(59)

tert-Butyl (6(2(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hex-5-yn-1-yl)carbamate

To a solution of4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (672 mg, 2mmol) and tert-butyl hex-5-yn-1-ylcarbamate (788 mg, 4 mmol) in DMF (10mL) were added CuI (76 mg, 0.4 mmol), Et₃N (5 mL) and Pd(PPh₃)₂Cl₂ (140mg, 0.2 mmol). The resulting mixture was then heated up to 70° C. andstirred under N2 atmosphere for 3 h. The mixture was then filtered,concentrated in vacuo, and purified by silica gel (MeOH/DCM=0-6%) toprovide the title compound.

LCMS (m/z): 454 [M+H]⁺.

tert-Butyl(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexyl)carbamate

To a solution of tert-butyl(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hex-5-yn-1-yl)carbamatein MeOH was added Pd/C (10 wt. % loading, matrix carbon), then themixture was hydrogenated at room temperature overnight. The reactionmixture was filtered and the filtrate was concentrated in vacuo toprovide the title compound.

LCMS (m/z): 458 [M+H]⁺.

4-(6-Aminohexyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

A solution of tert-Butyl(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexyl)carbamatein TFA/DCM=1/2 (v/v) was stirred at room temperature for 3 h, and thenconcentrated in vacuo. The crude title compound was used in the nextstep without any purification.

LCMS (m/z): 358 [M+H]⁺.

4-(6-((2-Chloropyrimidin-4-yl)amino)hexyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of4-(6-aminohexyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione and2,4-dichloropyrimidine (1 eq) in isopropanol was added DIEA (3 eq), andthen the mixture was stirred at 50° C. for 3 h. The mixture was thenconcentrated in vacuo, purified by silica gel (MeOH/DCM=0-10%) toprovide the title compound (120 mg).

LCMS (m/z): 470 [M+H]⁺.

To a solution of4-(6-((2-Chloropyrimidin-4-yl)amino)hexyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(40 mg, 0.085 mmol) and 2,3-dihydro-1H-inden-5-amine (11 mg, 0.085 mmol)in ^(t)BuOH (2 mL) was added TFA (13 μL, 0.17 mmol), then the mixturewas stirred at 100° C. overnight. The mixture was concentrated in vacuoand purified by prep-HPLC to provide compound 59 (3.2 mg, 6%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.12 (d, J=3.5 Hz, 1H), 8.83 (s, 1H),7.97-7.62 (m, 5H), 7.42 (s, 1H), 7.08-6.99 (m, 1H), 6.65-6.57 (m, 1H),5.94-5.85 (m, 1H), 5.22-5.06 (m, 1H), 2.90 (ddd, J=16.9, 13.8, 5.4 Hz,1H), 2.77 (td, J=15.8, 13.9, 7.2 Hz, 4H), 2.61 (d, J=19.1 Hz, 1H), 2.34(dt, J=46.4, 7.0 Hz, 2H), 2.13-2.03 (m, 1H), 2.03-1.90 (m, 2H),1.69-1.49 (m, 4H), 1.38 (d, J=18.4 Hz, 2H).

LCMS (m/z): 567 [M+H]⁺.

Example 58: Synthesis of4-(6-((2-((9H-fluoren-2-yl)amino)pyrimidin-4-yl)amino)hexyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(60)

To a solution of4-(6-aminohexyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione and2,4-dichloropyrimidin (40 mg, 0.085 mmol) and 9H-fluoren-3-amine (15 mg,0.085 mmol) in ^(t)BuOH (2 mL) was added TFA (13 μL, 0.17 mmol), thenthe mixture was stirred at 100° C. overnight. The mixture wasconcentrated in vacuo and purified by prep-HPLC to provide compound 60.(5.6 mg, 9%).

LCMS (m/z): 615 [M+H]⁺.

Example 59: Synthesis of2-(2,6-dioxopiperidin-3-yl)-4-(6-((2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)pyrimidin-4-yl)amino)hexyl)isoindoline-1,3-dione(61)

To a solution of4-(6-aminohexyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione and2,4-dichloropyrimidin (40 mg, 0.085 mmol) and1-(3-(trifluoromethyl)phenyl)piperazine (19 mg, 0.085 mmol) in BuOH (2mL) was added TFA (13 μL, 0.17 mmol), then the mixture was stirred at100° C. overnight. The mixture was concentrated in vacuo and purified byprep-HPLC to provide compound 61 (5.5 mg, 8%).

¹H NMR (500 MHz, DMSO-d₆) δ 11.30-10.99 (m, 1H), 8.84 (s, 1H), 8.00-7.75(m, 3H), 7.70 (td, J=6.7, 2.4 Hz, 1H), 7.48-7.40 (m, 1H), 7.22 (s, 1H),7.10 (d, J=3.4 Hz, 1H), 6.68-6.60 (m, 1H), 6.18-6.07 (m, 1H), 5.14 (ddd,J=13.2, 5.2, 3.3 Hz, 1H), 3.85 (d, J=5.6 Hz, 4H), 3.48 (s, 4H),2.98-2.85 (m, 1H), 2.67-2.55 (m, 1H), 2.31 (q, J=6.9 Hz, 1H), 2.05 (dt,J=11.6, 5.0 Hz, 1H), 1.71-1.49 (m, 4H), 1.24 (s, 4H).

LCMS (m/z): 664 [M+H]⁺.

Example of 60: Synthesis of3-(5-(((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(41)

To a solution of2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (67 mg,0.19 mmol) and3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TFA (50 mg,0.13 mmol) in DMA (2 mL), DIEA (67 mg, 0.52 mmol) was added at roomtemperature. The reaction mixture was heated up to 130° C. overnight.The crude mixture was purified by HPLC to yield compound 41 (18 mg,0.031 mmol, 24%).

¹H NMR (500 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.50 (s, 1H), 8.30-7.93 (m,3H), 7.90-7.54 (m, 3H), 7.50-7.27 (m, 3H), 5.09 (dd, J=13.3, 5.1 Hz,1H), 4.54 (d, J=48.2 Hz, 2H), 4.42-4.16 (m, 2H), 3.39 (d, J=58.0 Hz,1H), 2.90 (ddd, J=17.3, 13.6, 5.5 Hz, 1H), 2.59 (dd, J=17.1, 3.8 Hz,1H), 2.37 (qd, J=13.2, 4.4 Hz, 1H), 1.14 (m, 6H).

LCMS (m/z): 583 [M+H]⁺.

Example 61: Synthesis of3-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione(42)

To a solution of2,5-dichloro-N-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (67 mg,0.19 mmol) and Lenalidomide (50 mg, 0.19 mmol) in s-BuOH (2 mL), TFA (33mg, 0.29 mmol) was added at room temperature. The reaction mixture washeated up to 100° C. overnight. The crude mixture was purified by HPLCto yield compound 42 (21 mg, 0.037 mmol, 19%). (M+H)⁺ calculated:569.13, found 569.14.

¹H NMR (500 MHz, DMSO-d₆) δ 10.97 (s, 1H), 9.60 (s, 1H), 9.43 (s, 1H),8.47 (d, J=8.4 Hz, 1H), 8.29 (s, 1H), 7.82 (td, J=7.7, 7.1, 2.1 Hz, 2H),7.61-7.46 (m, 3H), 7.35-7.26 (m, 1H), 5.10 (dd, J=13.3, 5.1 Hz, 1H),4.51-4.28 (m, 2H), 3.47 (p, J=6.8 Hz, 1H), 2.87 (ddd, J=17.3, 13.7, 5.4Hz, 1H), 2.54 (d, J=4.0 Hz, 1H), 2.28 (qd, J=13.3, 4.5 Hz, 1H),1.88-1.76 (m, 1H), 1.17 (dd, J=10.0, 6.8 Hz, 6H).

LCMS (m/z): 569 [M+H]⁺.

Example 62: Lenalidomide Displacement Assay

Various inventive compounds were analyzed for cereblon binding.Compounds in an Atto565-Lenalidomide displacement assay were dispensedin a 384-well microplate (Corning, 4514) using D300e Digital Dispenser(HP) normalized to 1% DMSO into 10 nM Atto565-Leanlidomide, 100 nMDDB1ΔB-CRBN, 50 mM Tris pH 7.5, 200 mM NaCl, 0.1% Pluronic® F-68solution (Sigma). Compound titrations were incubated for 60 min at roomtemperature. The change in fluorescence polarization was monitored usinga PHERAstar® FS microplate reader (BMG Labtech) for 1 h in 120s cycles.Data from two independent replicates (n=2) was used to estimate IC₅₀values using variable slope equation in GraphPad Prism 7. The Ki wascalculated with probe Kd of 40 nM for the conditions described abovefollowing equations described in Nikolovska-Coleska et al., AnalyticalBiochemistry 332(2): 261-273 (2004) for competitive model using freeconcentrations.

The results, shown in IC₅₀ and Ki values, are set forth below in Table1.

Example 63: Cellular CRBN dBET6 Displacement Assay

BRD4BD2 were subcloned into mammalian pcDNA5/FRT Vector (Ampicillin andHygromycin B resistant) modified to contain MCS-eGFP-P2A-mCherry. Stablecell lines expressing eGFP-protein fusion and mCherry reporter weregenerated using the Flip-In™ 293 system. Plasmid (0.3 μg) and pOG44 (4.7μg) DNA were preincubated in 100 μl of Opti-MEM I (Gibco™, LifeTechnologies™) media containing 0.05 mg/ml Lipofectamine® 2000(Invitrogen™) for 20 minutes and added to Flip-In™ 293 cells containing1.9 ml of DMEM media (Gibco™, Life Technologies™) per well in a 6-wellplate format (Falcon®, 353046). Cells were propagated after 48 hours andtransferred into a 10 cm2 plate (Corning, 430165) in DMEM mediacontaining 50 μg/ml of Hygromycin B (REF 10687010, Invitrogen™) as aselection marker. Following a 2-3 passage cycle, FACS (FACSAria™ II, BD)was used to enrich for cells expressing eGFP and mCherry.

Cells stably expressing BRD4BD2-GFP with mCherry reporter were seeded at30-50% confluency in 96 well plates (3596, Costar) with 100 μl DMEMmedia containing 10% FBS per well a day before compound treatment.Compounds and 100 nM dBET6 were dispensed using D300e Digital Dispenser(HP) normalized to 0.5% DMSO and incubated with cells for 5 hoursfollowing trypsinization and resuspension in DMEM media, transferredinto 96-well plates (353910, Falcon®) and analyzed by flow cytometer(guava easyCyte™ HT, Millipore™). Signal from minimal 3000 events perwell was acquired and the eGFP and mCherry florescence monitored. Datawas analyzed using FlowJo® (FlowJo®, LCC). Forward and side scatteroutliers, frequently associated with cell debris, were removedleaving >90% of total cells, followed by removal of eGFP and mCherrysignal outliers, leaving 88-90% of total cells creating the set used forquantification. The eGFP protein abundance relative to mCherry was thenquantified as a ten-fold amplified ratio for each individual cell usingthe formula: 10×eGFP/mCherry. The median of the ratio was thencalculated per set, normalized to the median of the DMSO ratio.

TABLE 1 Characterization of compounds with in vitro CRBN binding,CRBN-dependent proliferation, and cellular engagement assays. CellularCRBN CRBN CRBN-BRD4 Binding Binding dBET6 displacement Compound IC₅₀ μMKi μM EC₅₀ μM Lenalidomide 5.19 1.49 0.82 1 29.7 8.5 2 47.5 13.6 47.93 312.5 13.6 4 8.5 2.4 5 42.5 12.2 6 22.9 6.5 7 38.9 11.1 8 N N 9 22.1 6.310 18.9 5.4 11 14.7 4.2 12 13.8 3.9 13 28.9 8.3 14 1.6 0.44 15 15.2 4.316 0.517 0.13 17 3.44 0.97 18 2.694 19 3.63 20 1.264 21 2.311 22 Notbinding 23 0.66 24 1.347 25 26 0.67 27 1.246 28 3.247 29 8.138 30 8.14631 8.66 32 4.164 33 2.594 34 Not binding 35 1.86 36 2.24 37 9.737 382.604 39 0.742 40 Not binding 41 42 43 25.27 44 0.913 45 2.06 46 1.12747 27.07 48 12.45 49 12.42 50 8.29 51 6.83 52 0.46 53 0.665

As shown in Table 1, compounds 1-17 that share the same amine basedlinkage to the lenalidomide moiety bound CRBN in vitro with the K_(i) inthe range of 13 to 0.13 μM. Compound 14 and 16 and 17 showed affinitythat exceeds that of lenalidomide (K_(i) 1.49 μM).

These molecules were further assessed in a cellular CRBN engagementassay, which relies on displacement of CRBN-based degrader moleculedBET6 from CRBN by a competing ligand, hence a rescue in degradation ofsecond bromodomain of BRD4. This assay provided a readout of cellularCRBN binding impacted by the permeability of the molecule tested. Datais shown in Table 1.

As indicated in the Table 1, cellular CRBN engagement varied frominactive compounds (compounds 22, 34, 40) to compounds with EC₅₀exceeding that of FDA approved lenalidomide (EC₅₀ of 0.82 μM) forcompounds 23, 26, 39, 52 with EC₅₀ of 0.66, 0.67, 0.742, 0.46 M,respectively. The same pyrimidine-based attachment of IMiD core isshared by the most potent compounds, compounds 23, 26, 39 and 52. Theremaining compounds tested in this assay showed good to moderatecellular CRBN engagement as compared to that of lenalidomide.

All patent publications and non-patent publications are indicative ofthe level of skill of those skilled in the art to which this inventionpertains. All these publications are herein incorporated by reference tothe same extent as if each individual publication were specifically andindividually indicated as being incorporated by reference.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

1. A compound having a structure represented by formula (I):

wherein Z represents CH₂ or C(O); m and m¹ are independently an integerfrom 0-8; R is H or A; X is H or C(O); Y is absent or NR₁A wherein R₁ isH or C1-C2 alkyl, and wherein if R is H, then X is C(O), m¹ is 1 and Yis NR₁A; and if R is A, then X is H, m¹ is 0 and Y is absent; andwherein A represents a group selected from (A1)-(A5):

wherein R₂ is H or C1-C2 alkyl; R₃ is optionally substituted C1-C5alkyl, optionally substituted C6-C14 aryl, optionally substituted C6-C14heteroaryl, optionally substituted C5-C14 carbocyclic or optionallysubstituted C5-C14 heterocyclic, or R₂ and R₃ together with the N towhich they are bound form an optionally substituted C6-C14 heterocyclicgroup or an optionally substituted C6-C14 heteroaryl group;

wherein R₄ represents an optionally substituted cyclic group, e.g., anoptionally substituted C5-C14 carbocyclic group, an optionallysubstituted C6-C14 aryl group, an optionally substituted C5-C14heterocyclic group or an optionally substituted C6-C14 heteroaryl group;

wherein R₅ represents hydrogen or halo and R₆ represents NR₇R₈ whereinR₇ represents H and R₈ represents an optionally substituted C6-C14 arylgroup;

wherein R₂ and R₃ are as defined above, and R₉ and R₁₀ each represents Hor each independently represents C or N provided that at least one of R₉and R₁₀ represents N and together with the atoms to which they are boundform an optionally substituted C5-C6 heterocyclic or optionallysubstituted C6 heteroaryl group; or

wherein R₄, R₉ and R₁₀ are as defined above; or a pharmaceuticallyacceptable salt or stereoisomer thereof.
 2. The compound of claim 1,wherein m is 0, R is H, X is C(O), m¹ is 1, Y is NR₁A and R₁ is H, andthe compound of formula (I) has a structure represented by formula (Ia):

or a pharmaceutically acceptable salt or stereoisomer thereof.
 3. Thecompound of claim 2, wherein A is represented by A1, and the compound offormula (Ia) has a structure represented by formula (Ia1):

or a pharmaceutically acceptable salt or stereoisomer thereof.
 4. Thecompound of claim 3, wherein R₃ represents aryl or substituted aryl, andthe compound of formula (Ia1) has a structure represented by formula(Ia1a):

wherein m₁ is 0 or 1, and R₁₁ and R₁₂ independently represent H, halo,CF₃, or C1-C2 alkoxy, or wherein R₁₁ and R₁₂ each independentlyrepresents C or a heteroatom and together with the atoms to which theyare bound form an optionally substituted C5-C14 carbocyclic, optionallysubstituted C5-C14 heterocyclic, optionally substituted C6-C14 aryl oroptionally substituted C6-C14 heteroaryl group, or a pharmaceuticallyacceptable salt or stereoisomer thereof.
 5. The compound of claim 3,wherein R₃ represents an optionally substituted C5-C14 heterocyclicgroup, and the compound of formula (Ia1) has a structure represented byformula (Ia1b):

wherein R₁₃ is hydrogen or optionally substituted C1-C5 alkyl,optionally substituted C6-C14 aryl, optionally substituted C6-C14heteroaryl, optionally substituted C5-C14 carbocyclic or optionallysubstituted C5-C14 heterocyclic, or a pharmaceutically acceptable saltor stereoisomer thereof.
 6. The compound of claim 3, wherein m is 0 andR₂ and R₃ together with the atoms to which they are bound form anoptionally C5-C14 heterocyclic, and the compound of formula (Ia1) has astructure represented by formula (Ia1c):

or a pharmaceutically acceptable salt or stereoisomer thereof.
 7. Thecompound of claim 1, wherein A is represented by A2, and the compound offormula (Ia) has a structure represented by formula (Ia2):

or a pharmaceutically acceptable salt or stereoisomer thereof.
 8. Thecompound of claim 1, wherein m and m¹ is 0, X is H, Y is absent, and thecompound of formula (I) has a structure represented by formula (Ib):

or a pharmaceutically acceptable salt or stereoisomer thereof.
 9. Thecompound of claim 8, wherein A is represented by A1, and the compound offormula (I) has a structure represented by formula (Ib1):

or a pharmaceutically acceptable salt or stereoisomer thereof.
 10. Thecompound of claim 9, wherein R₃ is an optionally substituted C6-C14aryl, and the compound of formula (Ib1) has a structure represented byformula (Ib1a):

wherein m₁ is 0 or 1, or a pharmaceutically acceptable salt orstereoisomer thereof.
 11. The compound of claim 9, wherein the compoundof formula (Ib1) has a structure represented by formula (Ib1b):

wherein R₃ represents an optionally substituted C5-C14 heterocyclicgroup, or a pharmaceutically acceptable salt or stereoisomer thereof.12. The compound of claim 9, wherein R₂ and R₃ together with the atomsto which they are bound form an optionally substituted C5-C14heterocyclic group, and the compound of formula (Ib1) has a structurerepresented by formula (Ib1c):

or a pharmaceutically acceptable salt or stereoisomer thereof.
 13. Thecompound of claim 8, wherein A is represented by A2, and the compound offormula (Ib) has a structure represented by formula (Ib2):

or a pharmaceutically acceptable salt or stereoisomer thereof.
 14. Thecompound of claim 8, wherein A is represented by A3, and the compound offormula (Ib) has a structure represented by formula (Ib3):

or a pharmaceutically acceptable salt or stereoisomer thereof.
 15. Thecompound of claim 8, wherein A is represented by A4, and the compound offormula (Ib) has a structure represented by formula (Ib4):

or a pharmaceutically acceptable salt or stereoisomer thereof.
 16. Thecompound of claim 8, wherein A is represented by A5, and the compound offormula (Ib) has a structure represented by formula (Ib5):

or a pharmaceutically acceptable salt or stereoisomer thereof.
 17. Thecompound of claim 1, wherein X is H, m¹ is 0, R is A and Y is absent,and the compound of formula (I) has a structure represented by formula(Ic):

or a pharmaceutically acceptable salt or stereoisomer thereof.
 18. Thecompound of claim 17, wherein A is represented by A3, and the compoundof formula (Ic) has a structure represented by formula (Ic1):

or a pharmaceutically acceptable salt or stereoisomer thereof.
 19. Thecompound of claim 1, wherein R₃ represents an optionally substitutedC6-C14 aryl or an optionally substituted C6-14 heteroaryl group.
 20. Thecompound of claim 1, wherein R₃ represents an optionally substitutedC5-14 carbocyclic or an optionally substituted C5-14 heterocyclic group.21. The compound of claim 1, wherein R₄ represents an optionallysubstituted C6-14 aryl or an optionally substituted C6-14 heteroarylgroup.
 22. The compound of claim 1, wherein R₄ represents an optionallysubstituted C5-14 carbocyclic or an optionally substituted C5-14heterocyclic group.
 23. The compound of claim 1, wherein R₃ or R₄ is anoptionally substituted a C6-14 aryl group or a substituted C6-14heteroaryl group.
 24. The compound of claim 23, wherein R₃ or R₄ is anoptionally substituted phenyl group.
 25. The compound of claim 1,wherein Z is CH₂.
 26. The compound of claim 1, which is selected fromthe group consisting of:

or a pharmaceutically acceptable salt or stereoisomer thereof.
 27. Apharmaceutical composition comprising a therapeutically effective amountof the compound of claim 1 or a pharmaceutically acceptable salt orstereoisomer thereof, and a pharmaceutically acceptable carrier.
 28. Thepharmaceutically composition of claim 27, which is in the form of acapsule or tablet.
 29. The pharmaceutical composition of claim 27, whichis a solution or suspension.
 30. A method of treating a disease ordisorder characterized or mediated by aberrant activity of a proteinselected from the group consisting of casein kinase 1 alpha (CK1α),family with sequence similarity 83 member F (FAM83F), DTW domaincontaining 1 (DTWD1), zinc finger protein 91 homolog (ZFP91), ZFP62,ZFP36 ring finger protein like (ZFP36L2), ring finger protein 166(RNF166), Ikaros family zinc finger protein 1 (IKZF1), IKZF2, IKZF3,IKZF4, IKZF5, Ras-related protein Rab-28 (RAB28), glutathioneS-transferase pi 1 (GSTP1), GSPT2, mitochondrial import inner membranetranslocase subunit Tim10 (TIMM10), GDNF inducible zinc finger protein 1(GZF1), early growth response 1 (EGR1), hypermethylated in cancer 1(HIC1), HIC2, insulinoma-associated protein 2 (INSM2), odd-skippedrelated transcription factor 2 (OSR2), protein polybromo-1 (PB1), PRdomain zinc finger protein 15 (PRD15), spalt like transcription factor 1(SALL1), SALL3, SALL4, WIZ, zinc finger and BTB domain-containingprotein 17 (ZBT17), ZBT41, ZBT49, ZBT7A, ZBT7B, ZBTB2, ZBTB39, zincfinger protein interacting with K protein 1 (ZIK1), zinc finger protein3 (ZNF3), ZNF217, ZNF276, ZNF316, ZNF324B, ZNF335, ZNF397, ZNF407,ZNF408, ZNF462, ZNF483, SNF517, ZNF526, ZNF581, ZNF587, ZNF589, ZNF618,ZNF644, ZNF646, ZNF653, ZNF654, ZNF692, ZNF724, ZNF771, ZNF782, ZNF784,ZNF814, zinc finger and SCAN domain containing 10 (ZSC10), ZSC22, ZC827,and zinc finger with UFM1-specific peptidase domain (ZUFSP), comprisingadministering a therapeutically effective amount of the compound ofclaim 1, or a pharmaceutically acceptable salt or stereoisomer thereof,to a subject in need thereof.
 31. The method of claim 30, wherein thedisease or disorder is characterized or mediated by aberrant activity ofIKZF2.